Abstract
The sigma-1 receptor is a 223 amino acid-long protein with a recently identified structure. The sigma-2 receptor is a genetically unrelated protein with a similarly shaped binding pocket and acts to influence cellular activities similar to the sigma-1 receptor. Both proteins are highly expressed in neuronal tissues. As such, they have become targets for treating neurological diseases, including Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), multiple sclerosis (MS), Rett syndrome (RS), developmental and epileptic encephalopathies (DEE), and motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). In recent years, there have been many pre-clinical and clinical studies of sigma receptor (1 and 2) ligands for treating neurological disease. Drugs such as blarcamesine, dextromethorphan and pridopidine, which have sigma-1 receptor activity as part of their pharmacological profile, are effective in treating multiple aspects of several neurological diseases. Furthermore, several sigma-2 receptor ligands are under investigation, including CT1812, rivastigmine and SAS0132. This review aims to provide a current and up-to-date analysis of the current clinical and pre-clinical data of drugs with sigma receptor activities for treating neurological disease.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Hanner M, Moebius FF, Flandorfer A, Knaus HG, Striessnig J, Kempner E, et al. Purification, molecular cloning, and expression of the mammalian sigma1-binding site. Proc Natl Acad Sci USA. 1996;93(15):8072–7. https://doi.org/10.1073/pnas.93.15.8072.
Hayashi T, Su TP. σ-1 Receptors (σ1 binding sites) form raft-like microdomains and target lipid droplets on the endoplasmic reticulum: roles in endoplasmic reticulum lipid compartmentalization and export. J Pharmacol Exp Ther. 2003;306(2):718–25. https://doi.org/10.1124/jpet.103.051284.
Hayashi T, Su TP. Regulating ankyrin dynamics: roles of sigma-1 receptors. Proc Natl Acad Sci USA. 2001;98(2):491–6. https://doi.org/10.1073/pnas.021413698.
Kinoshita M, Matsuoka Y, Suzuki T, Mirrielees J, Yang J. Sigma-1 receptor alters the kinetics of Kv1.3 voltage gated potassium channels but not the sensitivity to receptor ligands. Brain Res. 2012;1452:1–9. https://doi.org/10.1016/j.brainres.2012.02.070.
Brimson JM, Akula KK, Abbas H, Ferry DR, Kulkarni SK, Russell ST, et al. Simple ammonium salts acting on sigma-1 receptors yield potential treatments for cancer and depression. Sci Rep. 2020;10(1):9251. https://doi.org/10.1038/s41598-020-65849-6.
Brimson JM, Brown CA, Safrany ST. Antagonists show GTP-sensitive high-affinity binding to the sigma-1 receptor. Br J Pharmacol. 2011;164(2B):772–80. https://doi.org/10.1111/j.1476-5381.2011.01417.x.
Natsvlishvili N, Goguadze N, Zhuravliova E, Mikeladze D. Sigma-1 receptor directly interacts with Rac1-GTPase in the brain mitochondria. BMC Biochem. 2015;16(1):1–7. https://doi.org/10.1186/s12858-015-0040-y.
Fontanilla D, Johannessen M, Hajipour AR, Cozzi NV, Jackson MB, Ruoho AE. The hallucinogen N, N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator. Science. 2009;323(5916):934–7. https://doi.org/10.1126/science.1166127.
Hayashi T, Su TP. Sigma-1 receptor ligands: potential in the treatment of neuropsychiatric disorders. CNS Drugs. 2004;18(5):269–84. https://doi.org/10.2165/00023210-200418050-00001.
Ruoho AE, Chu UB, Ramachandran S, Fontanilla D, Mavlyutov T, Hajipour AR. The ligand binding region of the sigma-1 receptor: studies utilizing photoaffinity probes, sphingosine and N-alkylamines. Curr Pharm Des. 2012;18(7):920–9. https://doi.org/10.2174/138161212799436584.
Vavers E, Zvejniece L, Maurice T, Dambrova M. Allosteric modulators of sigma-1 receptor: a review. Front Pharmacol. 2019;10:223. https://doi.org/10.3389/fphar.2019.00223.
Hayashi T, Su TP. The sigma receptor: evolution of the concept in neuropsychopharmacology. Curr Neuropharmacol. 2005;3(4):267–80. https://doi.org/10.2174/157015905774322516.
Quirion R, Chicheportiche R, Contreras PC, Johnson KM, Lodge D, Tam SW, et al. Classification and nomenclature of phencyclidine and sigma receptor sites. Trends Neurosci. 1987;10(11):444–6. https://doi.org/10.1016/0166-2236(87)90094-4.
Spruce BA, Campbell LA, McTavish N, Cooper MA, Appleyard MVL, O’Neill M, et al. Small molecule antagonists of the sigma-1 receptor cause selective release of the death program in tumor and self-reliant cells and inhibit tumor growth in vitro and in vivo. Cancer Res. 2004;64(14):4875–86. https://doi.org/10.1158/0008-5472.CAN-03-3180.
Wang L, Prescott AR, Spruce BA, Sanderson J, Duncan G. Sigma receptor antagonists inhibit human lens cell growth and induce pigmentation. Invest Ophthalmol Vis Sci. 2005;46(4):1403–8. https://doi.org/10.1167/iovs.04-1209.
Hayashi T, Su TP. Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca2+ signaling and cell survival. Cell. 2007;131(3):596–610. https://doi.org/10.1016/j.cell.2007.08.036.
Hellewell SB, Bruce A, Feinstein G, Orringer J, Williams W, Bowen WD. Rat liver and kidney contain high densities of σ1 and σ2 receptors: characterization by ligand binding and photoaffinity labeling. Eur J Pharmacol. 1994;268(1):9–18. https://doi.org/10.1016/0922-4106(94)90115-5.
Wolfe SA Jr, Culp SG, De Souza EB. σ-Receptors in endocrine organs: identification, characterization, and autoradiographic localization in rat pituitary, adrenal, testis, and ovary. Endocrinology. 1989;124(3):1160–72. https://doi.org/10.1210/endo-124-3-1160.
Borde P, Cosgrove N, Charmsaz S, Safrany ST, Young L. An investigation of Sigma-1 receptor expression and ligand-induced endoplasmic reticulum stress in breast cancer. Cancer Gene Ther. 2023;30(2):368–74. https://doi.org/10.1038/s41417-022-00552-4.
Huang YS, Lu HL, Zhang LJ, Wu Z. Sigma-2 receptor ligands and their perspectives in cancer diagnosis and therapy. Med Res Rev. 2014;34(3):532–66. https://doi.org/10.1002/med.21297.
Nicholson H, Mesangeau C, McCurdy CR, Bowen WD. Sigma-2 receptors play a role in cellular metabolism: stimulation of glycolytic hallmarks by CM764 in human SK-N-SH neuroblastoma. J Pharmacol Exp Ther. 2016;356(2):232–43. https://doi.org/10.1124/jpet.115.228387.
Rousseaux CG, Greene SF. Sigma receptors [σRs]: biology in normal and diseased states. J Recept Signal Transduct Res. 2016;36(4):327–88. https://doi.org/10.3109/10799893.2015.1015737.
Liu C, Yu CF, Wang SC, Li HY, Lin CM, Wang HH, et al. Sigma-2 receptor/TMEM97 agonist PB221 as an alternative drug for brain tumor. BMC Cancer. 2019;19(1):473. https://doi.org/10.1186/s12885-019-5700-7.
Yang K, Wang C, Sun T. The roles of intracellular chaperone proteins, sigma receptors, in Parkinson’s disease (PD) and major depressive disorder (MDD). Front Pharmacol. 2019;10:528. https://doi.org/10.3389/fphar.2019.00528.
Georgiadis MO, Karoutzou O, Foscolos AS, Papanastasiou I. Sigma receptor (σR) ligands with antiproliferative and anticancer activity. Molecules. 2017;22:9. https://doi.org/10.3390/molecules22091408.
Gebreselassie D, Bowen WD. Sigma-2 receptors are specifically localized to lipid rafts in rat liver membranes. Eur J Pharmacol. 2004;493(1–3):19–28. https://doi.org/10.1016/j.ejphar.2004.04.005.
Munro S. Lipid rafts: elusive or illusive? Cell. 2003;115(4):377–88. https://doi.org/10.1016/S0092-8674(03)00882-1.
Alon A, Lyu J, Braz JM, Tummino TA, Craik V, O’Meara MJ, et al. Structures of the σ2 receptor enable docking for bioactive ligand discovery. Nature. 2021;600(7890):759–64. https://doi.org/10.1038/s41586-021-04175-x.
Terada K, Migita K, Matsushima Y, Kamei C. Sigma-2 receptor as a potential therapeutic target for treating central nervous system disorders. Neural Regen Res. 2019;14(11):1893–4. https://doi.org/10.4103/1673-5374.259609.
Abate C, Niso M, Berardi F. Sigma-2 receptor: past, present and perspectives on multiple therapeutic exploitations. Future Med Chem. 2018;10(16):1997–2018. https://doi.org/10.4155/fmc-2018-0072.
Cantonero C, Camello PJ, Abate C, Berardi F, Salido GM, Rosado JA, et al. NO1, a new Sigma 2 receptor/TMEM97 fluorescent ligand, downregulates SOCE and promotes apoptosis in the triple negative breast cancer cell lines. Cancers (Basel). 2020;12(2):257. https://doi.org/10.3390/cancers12020257.
Zeng C, Vangveravong S, McDunn JE, Hawkins WG, Mach RH. Sigma-2 receptor ligand as a novel method for delivering a SMAC mimetic drug for treating ovarian cancer. Br J Cancer. 2013;109(9):2368–77. https://doi.org/10.1038/bjc.2013.593.
Zeng C, Riad A, Mach RH. The biological function of Sigma-2 receptor/TMEM97 and its utility in PET imaging studies in cancer. Cancers (Basel). 2020;12(7):1877. https://doi.org/10.3390/cancers12071877.
2021 Alzheimer's disease facts and figures. Alzheimers Dement. 2021;17(3):327–406. https://doi.org/10.1002/alz.12328.
Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med. 2010;362(4):329–44. https://doi.org/10.1056/NEJMra0909142.
Hyman BT. Amyloid-dependent and amyloid-independent stages of Alzheimer disease. Arch Neurol. 2011;68(8):1062–4. https://doi.org/10.1001/archneurol.2011.70.
Soria Lopez JA, González HM, Léger GC. Alzheimer’s disease. Handb Clin Neurol. 2019;167:231–55. https://doi.org/10.1016/b978-0-12-804766-8.00013-3.
Hampel H, Caraci F, Cuello AC, Caruso G, Nisticò R, Corbo M, et al. A path toward precision medicine for neuroinflammatory mechanisms in Alzheimer’s disease. Front Immunol. 2020;11:456. https://doi.org/10.3389/fimmu.2020.00456.
Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26(5):769–80. https://doi.org/10.1038/s41591-020-0815-6.
Sánchez-Fernández C, Entrena JM, Baeyens JM, Cobos EJ. Sigma-1 receptor antagonists: a new class of neuromodulatory analgesics. Adv Exp Med Biol. 2017;964:109–32. https://doi.org/10.1007/978-3-319-50174-1_9.
Su TP, Hayashi T. Understanding the molecular mechanism of sigma-1 receptors: towards a hypothesis that sigma-1 receptors are intracellular amplifiers for signal transduction. Curr Med Chem. 2003;10(20):2073–80. https://doi.org/10.2174/0929867033456783.
De B, Nadal X, Portillo-salido E, Sánchez-arroyos R, Ovalle S, Palacios G, et al. Sigma-1 receptors regulate activity-induced spinal sensitization and neuropathic pain after peripheral nerve injury. Pain. 2009;145(3):294–303. https://doi.org/10.1016/j.pain.2009.05.013.
Nieto FR, Cendán CM, Sánchez-Fernández C, Cobos EJ, Entrena JM, Tejada MA, et al. Role of sigma-1 receptors in paclitaxel-induced neuropathic pain in mice. J Pain. 2012;13(11):1107–21. https://doi.org/10.1016/j.jpain.2012.08.006.
Zamanillo D, Romero L, Merlos M, Vela JM. Sigma 1 receptor: a new therapeutic target for pain. Eur J Pharmacol. 2013;716(1–3):78–93. https://doi.org/10.1016/j.ejphar.2013.01.068.
Kawamura K, Kimura Y, Tsukada H, Kobayashi T, Nishiyama S, Kakiuchi T, et al. An increase of sigma1 receptors in the aged monkey brain. Neurobiol Aging. 2003;24(5):745–52. https://doi.org/10.1016/S0197-4580(02)00152-5.
Wallace DR, Mactutus CF, Booze RM. Sigma binding sites identified by [3H] DTG are elevated in aged Fischer-344× Brown Norway (F1) rats. Synapse. 2000;35(4):311–3. https://doi.org/10.1002/(SICI)1098-2396(20000315)35:4%3c311::AID-SYN9%3e3.0.CO;2-5.
Ishiwata K, Kobayashi T, Kawamura K, Matsuno K. Age-related changes of the binding of [3H] SA4503 to sigma1 receptors in the rat brain. Ann Nucl Med. 2003;17(1):73–7. https://doi.org/10.1007/BF02988264.
Horsager J, Fedorova TD, Berge NV, Klinge MW, Knudsen K, Hansen AK, et al. Cardiac 11C-donepezil binding increases with age in healthy humans: potentially signifying Sigma-1 receptor upregulation. J Cardiovasc Pharmacol Ther. 2019;24(4):365–70. https://doi.org/10.1177/1074248419838509.
Norbury R, Travis MJ, Erlandsson K, Waddington W, Owens J, Pimlott S, et al. In vivo imaging of muscarinic receptors in the aging female brain with (R, R)[123I]-I-QNB and single photon emission tomography. Exp Gerontol. 2005;40(3):137–45. https://doi.org/10.1016/j.exger.2004.10.002.
Sheline YI, Mintun MA, Moerlein SM, Snyder AZ. Greater loss of 5-HT2A receptors in midlife than in late life. Am J Psychiatry. 2002;159(3):430–5. https://doi.org/10.1176/appi.ajp.159.3.430.
Inoue M, Suhara T, Sudo Y, Okubo Y, Yasuno F, Kishimoto T, et al. Age-related reduction of extrastriatal dopamine D2 receptor measured by PET. Life Sci. 2001;69(9):1079–84. https://doi.org/10.1016/s0024-3205(01)01205-x.
Brimson JM, Brimson S, Chomchoei C, Tencomnao T. Using Sigma-ligands as part of a multi-receptor approach to target diseases of the brain. Expert Opin Ther Targets. 2020;24(10):1009–28. https://doi.org/10.1080/14728222.2020.1805435.
Prasanth MI, Malar D, Tencomnao T, Brimson J. The emerging role of the sigma-1 receptor in autophagy: hand-in-hand targets for the treatment of Alzheimer’s Disease. Expert Opin Ther Targets. 2021;25(5):401–14. https://doi.org/10.1080/14728222.2021.1939681.
Mishina M, Ohyama M, Ishii K, Kitamura S, Kimura Y, Oda K, et al. Low density of sigma 1 receptors in early Alzheimer’s disease. Ann Nucl Med. 2008;22(3):151–6. https://doi.org/10.1007/s12149-007-0094-z.
Minoshima S, Giordani B, Berent S, Frey KA, Foster NL, Kuhl DE. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease. Ann Neurol. 1997;42(1):85–94. https://doi.org/10.1002/ana.410420114.
Uchida N, Ujike H, Tanaka Y, Sakai A, Yamamoto M, Fujisawa Y, et al. A variant of the sigma receptor type-1 gene is a protective factor for Alzheimer disease. Am J Geriatr Psychiatry. 2005;13(12):1062–6. https://doi.org/10.1176/appi.ajgp.13.12.1062.
Maruszak A, Safranow K, Gacia M, Gabryelewicz T, Słowik A, Styczyńska M, et al. Sigma receptor type 1 gene variation in a group of polish patients with Alzheimer’s disease and mild cognitive impairment. Dement Geriatr Cogn Disord. 2007;23(6):432–8. https://doi.org/10.1159/000101990.
Huang Y, Zheng L, Halliday G, Dobson-Stone C, Wang Y, Tang H-D, et al. Genetic polymorphisms in sigma-1 receptor and apolipoprotein E interact to influence the severity of Alzheimer’s disease. Curr Alzheimer Res. 2011;8(7):765–70. https://doi.org/10.2174/156720511797633232.
Feher A, Juhasz A, Laszlo A, Kalman J Jr, Pakaski M, Kalman J, et al. Association between a variant of the sigma-1 receptor gene and Alzheimer’s disease. Neurosci Lett. 2012;517(2):136–9. https://doi.org/10.1016/j.neulet.2012.04.046.
Jin JL, Fang M, Zhao YX, Liu XY. Roles of sigma-1 receptors in Alzheimer’s disease. Int J Clin Exp Med. 2015;8(4):4808–20.
Tsai SY, Hayashi T, Harvey BK, Wang Y, Wu WW, Shen RF, et al. Sigma-1 receptors regulate hippocampal dendritic spine formation via a free radical-sensitive mechanism involving Rac1•GTP pathway. Proc Natl Acad Sci USA. 2009;106(52):22468–73. https://doi.org/10.1073/pnas.0909089106.
Fisher A, Bezprozvanny I, Wu L, Ryskamp DA, Bar-Ner N, Natan N, et al. AF710B, a novel M1/σ1 agonist with therapeutic efficacy in animal models of Alzheimer’s disease. Neurodegener Dis. 2016;16(1–2):95–110. https://doi.org/10.1159/000440864.
Ryskamp D, Wu L, Wu J, Kim D, Rammes G, Geva M, et al. Pridopidine stabilizes mushroom spines in mouse models of Alzheimer’s disease by acting on the sigma-1 receptor. Neurobiol Dis. 2019;124:489–504. https://doi.org/10.1016/j.nbd.2018.12.022.
Tsai SYA, Pokrass MJ, Klauer NR, Nohara H, Su TP. Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid. Proc Natl Acad Sci USA. 2015;112(21):6742–7. https://doi.org/10.1073/pnas.1422001112.
Christ MG, Huesmann H, Nagel H, Kern A, Behl C. Sigma-1 receptor activation induces autophagy and increases proteostasis capacity in vitro and in vivo. Cells. 2019;8(3):211. https://doi.org/10.3390/cells8030211.
Romeo MA, Faggioni A, Cirone M. Could autophagy dysregulation link neurotropic viruses to Alzheimer’s disease? Neural Regen Res. 2019;14(9):1503–6. https://doi.org/10.4103/1673-5374.253508.
McBrayer M, Nixon RA. Lysosome and calcium dysregulation in Alzheimer’s disease: partners in crime. Biochem Soc Trans. 2013;41(6):1495–502. https://doi.org/10.1042/BST20130201.
Uddin MS, Stachowiak A, Mamun AA, Tzvetkov NT, Takeda S, Atanasov AG, et al. Autophagy and Alzheimer’s disease: from molecular mechanisms to therapeutic implications. Front Aging Neurosci. 2018;10:04. https://doi.org/10.3389/fnagi.2018.00004.
Callens M, Loncke J, Bultynck G. Dysregulated Ca2+ homeostasis as a central theme in neurodegeneration: lessons from Alzheimer’s disease and Wolfram syndrome. Cells. 2022;11(12):1963. https://doi.org/10.3390/cells11121963.
Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, et al. Long-term effects of Aβ42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet. 2008;372(9634):216–23. https://doi.org/10.1016/S0140-6736(08)61075-2.
van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9–21. https://doi.org/10.1056/NEJMoa2212948.
Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, et al. Aβ oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci. 2007;27(4):796–807. https://doi.org/10.1523/JNEUROSCI.3501-06.2007.
Pannuzzo M. On the physiological/pathological link between Aβ peptide, cholesterol, calcium ions and membrane deformation: a molecular dynamics study. Biochim Biophys Acta. 2016;1858(6):1380–9. https://doi.org/10.1016/j.bbamem.2016.03.018.
Games D, Adams D, Alessandrini R, Barbour R, Borthelette P, Blackwell C, et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature. 1995;373(6514):523–7. https://doi.org/10.1038/373523a0.
Brimson JM. The Pharmacology of the Sigma-1 Receptor [Doctoral Thesis]. In: The University of Bath online repository. 2010. http://opus.bath.ac.uk/19712/. Accessed 1 Dec 2022.
Katnik C, Guerrero WR, Pennypacker KR, Herrera Y, Cuevas J. Sigma-1 receptor activation prevents intracellular calcium dysregulation in cortical neurons during in vitro ischemia. J Pharmacol Exp Ther. 2006;319(3):1355–65. https://doi.org/10.1124/jpet.106.107557.
Delprat B, Crouzier L, Su TP, Maurice T. At the crossing of ER stress and MAMs: a key role of sigma-1 receptor? Adv Exp Med Biol. 2020;1131:699–718. https://doi.org/10.1007/978-3-030-12457-1_2878.
Hayashi T, Rizzuto R, Hajnoczky G, Su TP. MAM: more than just a housekeeper. Trends Cell Biol. 2009;19(2):81–8. https://doi.org/10.1016/j.tcb.2008.12.00279.
Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):512–21. https://doi.org/10.1111/epi.13709.
Specchio N, Curatolo P. Developmental and epileptic encephalopathies: what we do and do not know. Brain. 2021;144(1):32–43. https://doi.org/10.1093/brain/awaa371.
Raga S, Specchio N, Rheims S, Wilmshurst JM. Developmental and epileptic encephalopathies: recognition and approaches to care. Epileptic Disord. 2021;23(1):40–52. https://doi.org/10.1684/epd.2021.1244.
Scheffer IE, Liao J. Deciphering the concepts behind “Epileptic encephalopathy” and “Developmental and epileptic encephalopathy.” Eur J Paediatr Neurol. 2020;24:11–4. https://doi.org/10.1016/j.ejpn.2019.12.023.
Trivisano M, Specchio N. What are the epileptic encephalopathies? Curr Opin Neurol. 2020;33(2):179–84. https://doi.org/10.1097/wco.0000000000000793.
EPX-100 (Clemizole Hydrochloride) as add-on therapy to control convulsive seizures in patients with Dravet syndrome (ARGUS). In: NIH U.S. National Library of Medicine. 2020. https://clinicaltrials.gov/ct2/show/NCT04462770. Accessed 1 Dec 2022.
Griffin A, Hamling KR, Knupp K, Hong S, Lee LP, Baraban SC. Clemizole and modulators of serotonin signalling suppress seizures in Dravet syndrome. Brain. 2017;140(3):669–83. https://doi.org/10.1093/brain/aww342.
Vasquez A, Buraniqi E, Wirrell EC. New and emerging pharmacologic treatments for developmental and epileptic encephalopathies. Curr Opin Neurol. 2022;35(2):145–54. https://doi.org/10.1097/wco.0000000000001029.
Miziak B, Czuczwar S. Advances in the design and discovery of novel small molecule drugs for the treatment of Dravet Syndrome. Expert Opin Drug Discov. 2021;16(5):579–93. https://doi.org/10.1080/17460441.2021.1857722.
Samanta D. Changing landscape of Dravet syndrome management: an overview. Neuropediatrics. 2020;51(2):135–45. https://doi.org/10.1055/s-0040-1701694.
Martin P, Reeder T, Sourbron J, de Witte PAM, Gammaitoni AR, Galer BS. An emerging role for Sigma-1 receptors in the treatment of developmental and epileptic encephalopathies. Int J Mol Sci. 2021;22(16):8416. https://doi.org/10.3390/ijms22168416.
Vavers E, Zvejniece B, Stelfa G, Svalbe B, Vilks K, Kupats E, et al. Genetic inactivation of the sigma-1 chaperone protein results in decreased expression of the R2 subunit of the GABA-B receptor and increased susceptibility to seizures. Neurobiol Dis. 2021;150:105244. https://doi.org/10.1016/j.nbd.2020.105244.
Schaffar G, Breuer P, Boteva R, Behrends C, Tzvetkov N, Strippel N, et al. Cellular toxicity of polyglutamine expansion proteins: mechanism of transcription factor deactivation. Mol Cell. 2004;15(1):95–105. https://doi.org/10.1016/j.molcel.2004.06.029.
Martinez-Vicente M, Talloczy Z, Wong E, Tang G, Koga H, Kaushik S, et al. Cargo recognition failure is responsible for inefficient autophagy in Huntington’s disease. Nat Neurosci. 2010;13(5):567–76. https://doi.org/10.1038/nn.2528.
Mochel F, Haller RG. Energy deficit in Huntington disease: why it matters. J Clin Invest. 2011;121(2):493–9. https://doi.org/10.1172/JCI45691.
Caron NS, Wright GEB, Hayden MR. Huntington Disease. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, et al., editors. GeneReviews, University of Washington, Seattle. 1993. https://www.ncbi.nlm.nih.gov/books/NBK1305/.
Frank S. Treatment of Huntington’s disease. Neurotherapeutics. 2014;11(1):153–60. https://doi.org/10.1007/s13311-013-0244-z.
Miki Y, Tanji K, Mori F, Wakabayashi K. Sigma-1 receptor is involved in degradation of intranuclear inclusions in a cellular model of Huntington’s disease. Neurobiol Dis. 2015;74:25–31. https://doi.org/10.1016/j.nbd.2014.11.005.
Ryskamp D, Wu J, Geva M, Kusko R, Grossman I, Hayden M, et al. The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease. Neurobiol Dis. 2017;97:46–59. https://doi.org/10.1016/j.nbd.2016.10.006.
Jabłońska M, Grzelakowska K, Wiśniewski B, Mazur E, Leis K, Gałązka P. Pridopidine in the treatment of Huntington’s disease. Rev Neurosci. 2020;31(4):441–51. https://doi.org/10.1515/revneuro-2019-0085.
Nguyen L, Lucke-Wold BP, Mookerjee SA, Cavendish JZ, Robson MJ, Scandinaro AL, et al. Role of sigma-1 receptors in neurodegenerative diseases. J Pharmacol Sci. 2015;127(1):17–29. https://doi.org/10.1016/j.jphs.2014.12.005.
Swinnen B, Robberecht W. The phenotypic variability of amyotrophic lateral sclerosis. Nat Rev Neurol. 2014;10(11):661–70. https://doi.org/10.1038/nrneurol.2014.184.
Machts J, Keute M, Kaufmann J, Schreiber S, Kasper E, Petri S, et al. Longitudinal clinical and neuroanatomical correlates of memory impairment in motor neuron disease. Neuroimage Clin. 2021;29:102545. https://doi.org/10.1016/j.nicl.2020.102545.
Roggenbuck J, Quick A, Kolb SJ. Genetic testing and genetic counseling for amyotrophic lateral sclerosis: an update for clinicians. Genet Med. 2017;19(3):267–74. https://doi.org/10.1038/gim.2016.107.
van den Bos MAJ, Geevasinga N, Higashihara M, Menon P, Vucic S. Pathophysiology and diagnosis of ALS: insights from advances in neurophysiological techniques. Int J Mol Sci. 2019;20(11):2818. https://doi.org/10.3390/ijms20112818.
Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med. 1994;330(9):585–91. https://doi.org/10.1056/nejm199403033300901.
Heo YA. Sodium phenylbutyrate and ursodoxicoltaurine: first approval. CNS Drugs. 2022;36(9):1007–13. https://doi.org/10.1007/s40263-022-00945-x.
Jaiswal MK. Riluzole and edaravone: a tale of two amyotrophic lateral sclerosis drugs. Med Res Rev. 2019;39(2):733–48. https://doi.org/10.1002/med.21528.
Mora JS, Genge A, Chio A, Estol CJ, Chaverri D, Hernández M, et al. Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial. Amyotroph Lateral Scler Frontotemporal Degener. 2020;21(1–2):5–14. https://doi.org/10.1080/21678421.2019.1632346.
Latham BD, Oskin DS, Crouch RD, Vergne MJ, Jackson KD. Cytochromes P450 2C8 and 3A catalyze the metabolic activation of the tyrosine kinase inhibitor masitinib. Chem Res Toxicol. 2022;35(9):1467–81. https://doi.org/10.1021/acs.chemrestox.2c00057.
Casanovas A, Salvany S, Lahoz V, Tarabal O, Piedrafita L, Sabater R, et al. Neuregulin 1-ErbB module in C-bouton synapses on somatic motor neurons: molecular compartmentation and response to peripheral nerve injury. Sci Rep. 2017;7:40155. https://doi.org/10.1038/srep40155.
Herrando-Grabulosa M, Gaja-Capdevila N, Vela JM, Navarro X. Sigma 1 receptor as a therapeutic target for amyotrophic lateral sclerosis. Br J Pharmacol. 2021;178(6):1336–52. https://doi.org/10.1111/bph.15224.
Mavlyutov TA, Epstein ML, Liu P, Verbny YI, Ziskind-Conhaim L, Ruoho AE. Development of the sigma-1 receptor in C-terminals of motoneurons and colocalization with the N, N′-dimethyltryptamine forming enzyme, indole-N-methyl transferase. Neuroscience. 2012;206:60–8. https://doi.org/10.1016/j.neuroscience.2011.12.040.
Mavlyutov TA, Epstein ML, Andersen KA, Ziskind-Conhaim L, Ruoho AE. The sigma-1 receptor is enriched in postsynaptic sites of C-terminals in mouse motoneurons. An anatomical and behavioral study. Neuroscience. 2010;167(2):247–55. https://doi.org/10.1016/j.neuroscience.2010.02.022.
Watanabe S, Ilieva H, Tamada H, Nomura H, Komine O, Endo F, et al. Mitochondria-associated membrane collapse is a common pathomechanism in SIGMAR 1-and SOD 1-linked ALS. EMBO Mol Med. 2016;8(12):1421–37. https://doi.org/10.15252/emmm.201606403.
Couly S, Khalil B, Viguier V, Roussel J, Maurice T, Liévens J-C. Sigma-1 receptor is a key genetic modulator in amyotrophic lateral sclerosis. Hum Mol Genet. 2020;29(4):529–40. https://doi.org/10.1093/hmg/ddz267.
Vollrath J, Sechi A, Dreser A, Katona I, Wiemuth D, Vervoorts J, et al. Loss of function of the ALS protein SigR1 leads to ER pathology associated with defective autophagy and lipid raft disturbances. Cell Death Dis. 2014;5(6):e1290. https://doi.org/10.1038/cddis.2014.243.
Dreser A, Vollrath JT, Sechi A, Johann S, Roos A, Yamoah A, et al. The ALS-linked E102Q mutation in Sigma receptor-1 leads to ER stress-mediated defects in protein homeostasis and dysregulation of RNA-binding proteins. Cell Death Differ. 2017;24(10):1655–71. https://doi.org/10.1038/cdd.2017.88.
Mavlyutov TA, Epstein ML, Verbny YI, Huerta MS, Zaitoun I, Ziskind-Conhaim L, et al. Lack of sigma-1 receptor exacerbates ALS progression in mice. Neuroscience. 2013;240:129–34. https://doi.org/10.1016/j.neuroscience.2013.02.035.
Al-Saif A, Al-Mohanna F, Bohlega S. A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis. Ann Neurol. 2011;70(6):913–9. https://doi.org/10.1002/ana.22534.
Fukunaga K, Shinoda Y, Tagashira H. The role of SIGMAR1 gene mutation and mitochondrial dysfunction in amyotrophic lateral sclerosis. J Pharmacol Sci. 2015;127(1):36–41. https://doi.org/10.1016/j.jphs.2014.12.012.
Barmada SJ, Skibinski G, Korb E, Rao EJ, Wu JY, Finkbeiner S. Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis. J Neurosci. 2010;30(2):639–49. https://doi.org/10.1523/JNEUROSCI.4988-09.2010.
Prasad A, Bharathi V, Sivalingam V, Girdhar A, Patel BK. Molecular mechanisms of TDP-43 misfolding and pathology in amyotrophic lateral sclerosis. Front Mol Neurosci. 2019;12:25. https://doi.org/10.3389/fnmol.2019.00025.
Brettschneider J, Del Tredici K, Toledo JB, Robinson JL, Irwin DJ, Grossman M, et al. Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Ann Neurol. 2013;74(1):20–38. https://doi.org/10.1002/ana.23937.
Lee P-T, Liévens J-C, Wang S-M, Chuang J-Y, Khalil B, Wu H-E, et al. Sigma-1 receptor chaperones rescue nucleocytoplasmic transport deficit seen in cellular and Drosophila ALS/FTD models. Nat Commun. 2020;11(1):5580. https://doi.org/10.1038/s41467-020-19396-3.
Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009;132(Pt 5):1175–89. https://doi.org/10.1093/brain/awp070.
McGinley MP, Goldschmidt CH, Rae-Grant AD. Diagnosis and treatment of multiple sclerosis: a review. JAMA. 2021;325(8):765–79. https://doi.org/10.1001/jama.2020.26858.
Krupp L. Fatigue is intrinsic to multiple sclerosis (MS) and is the most commonly reported symptom of the disease. Mult Scler. 2006;12(4):367–8. https://doi.org/10.1191/135248506ms1373ed.
Braley TJ, Chervin RD. Fatigue in multiple sclerosis: mechanisms, evaluation, and treatment. Sleep. 2010;33(8):1061–7. https://doi.org/10.1093/sleep/33.8.1061.
Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med. 2000;343(13):898–904. https://doi.org/10.1056/nejm200009283431301.
Lycke J. Monoclonal antibody therapies for the treatment of relapsing-remitting multiple sclerosis: differentiating mechanisms and clinical outcomes. Ther Adv Neurol Disord. 2015;8(6):274–93. https://doi.org/10.1177/1756285615605429.
Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, Calabresi P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387–401. https://doi.org/10.1056/NEJMoa0909494.
Kappos L, Bar-Or A, Cree BAC, Fox RJ, Giovannoni G, Gold R, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018;391(10127):1263–73. https://doi.org/10.1016/s0140-6736(18)30475-6.
Comi G, Kappos L, Selmaj KW, Bar-Or A, Arnold DL, Steinman L, et al. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol. 2019;18(11):1009–20. https://doi.org/10.1016/s1474-4422(19)30239-x.
Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1995;45(7):1268–76. https://doi.org/10.1212/wnl.45.7.1268.
Confavreux C, O’Connor P, Comi G, Freedman MS, Miller AE, Olsson TP, et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13(3):247–56. https://doi.org/10.1016/s1474-4422(13)70308-9.
Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, Soelberg Sørensen P, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):416–26. https://doi.org/10.1056/NEJMoa0902533.
Palacios G, Muro A, Verdú E, Pumarola M, Vela JM. Immunohistochemical localization of the sigma1 receptor in Schwann cells of rat sciatic nerve. Brain Res. 2004;1007(1–2):65–70. https://doi.org/10.1016/j.brainres.2004.02.013.
Hayashi T, Su T-P. Sigma-1 receptors at galactosylceramide-enriched lipid microdomains regulate oligodendrocyte differentiation. Proc Natl Acad Sci USA. 2004;101(41):14949–54. https://doi.org/10.1073/pnas.0402890101.
Zhemkov V, Geva M, Hayden MR, Bezprozvanny I. Sigma-1 receptor (S1R) interaction with cholesterol: mechanisms of S1R activation and its role in neurodegenerative diseases. Int J Mol Sci. 2021;22(8):4082. https://doi.org/10.3390/ijms22084082.
Berghoff SA, Spieth L, Saher G. Local cholesterol metabolism orchestrates remyelination. Trends Neurosci. 2022;45(4):272–83. https://doi.org/10.1016/j.tins.2022.01.001.
Kenche H, Singh M, Smith J, Shen K. Neuronal mitochondrial dysfunction in a cellular model of circadian rhythm disruption is rescued by donepezil. Biochem Biophys Res Commun. 2021;567:56–62. https://doi.org/10.1016/j.bbrc.2021.06.029.
Oxombre B, Lee-Chang C, Duhamel A, Toussaint M, Giroux M, Donnier-Maréchal M, et al. High-affinity σ1 protein agonist reduces clinical and pathological signs of experimental autoimmune encephalomyelitis. Br J Pharmacol. 2015;172(7):1769–82. https://doi.org/10.1111/bph.13037.
Lotankar S, Prabhavalkar KS, Bhatt LK. Biomarkers for Parkinson’s disease: recent advancement. Neurosci Bull. 2017;33(5):585–97. https://doi.org/10.1007/s12264-017-0183-5.
Chen-Plotkin AS, Albin R, Alcalay R, Babcock D, Bajaj V, Bowman D, et al. Finding useful biomarkers for Parkinson’s disease. Sci Transl Med. 2018;10(454):eaam6003. https://doi.org/10.1126/scitranslmed.aam6003.
Li T, Le W. Biomarkers for Parkinson’s disease: how good are they? Neurosci Bull. 2020;36(2):183–94. https://doi.org/10.1007/s12264-019-00433-1.
Bloem BR, Okun MS, Klein C. Parkinson’s disease. Lancet. 2021;397(10291):2284–303. https://doi.org/10.1016/s0140-6736(21)00218-x.
Parkinson disease. In: World Health Organization website. 2022. https://www.who.int/news-room/fact-sheets/detail/parkinson-disease. Accessed 1 Dec 2022.
LeWitt PA. Levodopa therapy for Parkinson’s disease: pharmacokinetics and pharmacodynamics. Mov Disord. 2015;30(1):64–72. https://doi.org/10.1002/mds.26082.
Nonnekes J, Timmer MH, de Vries NM, Rascol O, Helmich RC, Bloem BR. Unmasking levodopa resistance in Parkinson’s disease. Mov Disord. 2016;31(11):1602–9. https://doi.org/10.1002/mds.26712.
Walker Z, Possin KL, Boeve BF, Aarsland D. Lewy body dementias. Lancet. 2015;386(10004):1683–97. https://doi.org/10.1016/S0140-6736(15)00462-6.
Aarsland D, Andersen K, Larsen J, Lolk A, Nielsen H, Kragh-Sørensen P. Risk of dementia in Parkinson’s disease: a community-based, prospective study. Neurology. 2001;56(6):730–6. https://doi.org/10.1212/wnl.56.6.730.
Mishina M, Ishiwata K, Ishii K, Kitamura S, Kimura Y, Kawamura K, et al. Function of sigma 1 receptors in Parkinson’s disease. Acta Neurol Scand. 2005;112(2):103–7. https://doi.org/10.1111/j.1600-0404.2005.00432.x.
Hong J, Wang L, Zhang T, Zhang B, Chen L. Sigma-1 receptor knockout increases α-synuclein aggregation and phosphorylation with loss of dopaminergic neurons in substantia nigra. Neurobiol Aging. 2017;59:171–83. https://doi.org/10.1016/j.neurobiolaging.2017.08.007.
Luo Y, Roth GS. The roles of dopamine oxidative stress and dopamine receptor signaling in aging and age-related neurodegeneration. Antioxid Redox Signal. 2000;2(3):449–60. https://doi.org/10.1089/15230860050192224.
Mori T, Hayashi T, Su TP. Compromising σ-1 receptors at the endoplasmic reticulum render cytotoxicity to physiologically relevant concentrations of dopamine in a nuclear factor-κB/Bcl-2-dependent mechanism: Potential relevance to Parkinson’s disease. J Pharmacol Exp Ther. 2012;341(3):663–71. https://doi.org/10.1124/jpet.111.190868.
Cagnin M, Ozzano M, Bellio N, Fiorentino I, Follo C, Isidoro C. Dopamine induces apoptosis in APPswe-expressing Neuro2A cells following Pepstatin-sensitive proteolysis of APP in acid compartments. Brain Res. 2012;1471:102–17. https://doi.org/10.1016/j.brainres.2012.06.025.
Brimson JM, Safrany ST, Qassam H, Tencomnao T. Dipentylammonium binds to the Sigma-1 receptor and protects against glutamate toxicity, attenuates dopamine toxicity and potentiates neurite outgrowth in various cultured cell lines. Neurotox Res. 2018;34(2):263–72. https://doi.org/10.1007/s12640-018-9883-5.
Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, et al. Parkinson disease. Nat Rev Dis Primers. 2017;3:17013. https://doi.org/10.1038/nrdp.2017.13.
Jenner P, Olanow CW. Oxidative stress and the pathogenesis of Parkinson’s disease. Neurology. 1996;47(6 Suppl 3):S161–70. https://doi.org/10.1212/wnl.47.6_suppl_3.161s.
Cristóvão AC, Guhathakurta S, Bok E, Je G, Yoo SD, Choi D-H, et al. NADPH oxidase 1 mediates α-synucleinopathy in Parkinson’s disease. J Neurosci. 2012;32(42):14465–77. https://doi.org/10.1523/JNEUROSCI.2246-12.2012.
Guo JD, Zhao X, Li Y, Li GR, Liu XL. Damage to dopaminergic neurons by oxidative stress in Parkinson’s disease. Int J Mol Med. 2018;41(4):1817–25. https://doi.org/10.3892/ijmm.2018.3406.
Pal A, Fontanilla D, Gopalakrishnan A, Chae Y-K, Markley JL, Ruoho AE. The sigma-1 receptor protects against cellular oxidative stress and activates antioxidant response elements. Eur J Pharmacol. 2012;682(1–3):12–20. https://doi.org/10.1016/j.ejphar.2012.01.030.
Wang J, Shanmugam A, Markand S, Zorrilla E, Ganapathy V, Smith SB. Sigma 1 receptor regulates the oxidative stress response in primary retinal Müller glial cells via NRF2 signaling and system xc−, the Na+-independent glutamate–cystine exchanger. Free Radic Biol Med. 2015;86:25–36. https://doi.org/10.1016/j.freeradbiomed.2015.04.009.
Prasanth MI, Tencomnao T, Brimson JM. The Sigma-1 receptors role in neuroprotection: Comment on Nrf2 as a therapeutic target in ischemic stroke. Expert Opin Ther Targets. 2021;25(7):613–4. https://doi.org/10.1080/14728222.2021.1948016.
Brimson JM, Prasanth MI, Isidoro C, Sukprasansap M, Tencomnao T. Cleistocalyx nervosum var. paniala seed extracts exhibit sigma-1 antagonist sensitive neuroprotective effects in PC12 cells and protect C. elegans from stress via the SKN-1/NRF-2 pathway. Nutr Healthy Aging. 2021;6(2):131–46. https://doi.org/10.3233/NHA-200108.
Brimson JM, Prasanth MI, Malar DS, Verma K, Plaingam W, Tencomnao T. Bacopa monnieri protects neuronal cell line and Caenorhabditis elegans models of Alzheimer’s disease through sigma-1 receptor antagonist sensitive and antioxidant pathways. Nutr Healthy Aging. 2022;7(3):173–96. https://doi.org/10.3233/NHA-220161.
Betzer C, Movius AJ, Shi M, Gai W-P, Zhang J, Jensen PH. Identification of synaptosomal proteins binding to monomeric and oligomeric α-synuclein. PLoS ONE. 2015;10(2):e0116473. https://doi.org/10.1371/journal.pone.0116473.
Schneider JL, Cuervo AM. Autophagy and human disease: emerging themes. Curr Opin Genet Dev. 2014;26:16–23. https://doi.org/10.1016/j.gde.2014.04.003.
Vogiatzi T, Xilouri M, Vekrellis K, Stefanis L. Wild type α-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. J Biol Chem. 2008;283(35):23542–56. https://doi.org/10.1074/jbc.M801992200.
Galvagnion C. The role of lipids interacting with α-synuclein in the pathogenesis of Parkinson’s disease. J Parkinsons Dis. 2017;7(3):433–50. https://doi.org/10.3233/JPD-171103.
Galvagnion C, Brown JW, Ouberai MM, Flagmeier P, Vendruscolo M, Buell AK, et al. Chemical properties of lipids strongly affect the kinetics of the membrane-induced aggregation of α-synuclein. Proc Natl Acad Sci USA. 2016;113(26):7065–70. https://doi.org/10.1073/pnas.1601899113.
Plotegher N, Berti G, Ferrari E, Tessari I, Zanetti M, Lunelli L, et al. DOPAL derived alpha-synuclein oligomers impair synaptic vesicles physiological function. Sci Rep. 2017;7:40699. https://doi.org/10.1038/srep40699.
Limegrover CS, Yurko R, Izzo NJ, LaBarbera KM, Rehak C, Look G, et al. Sigma-2 receptor antagonists rescue neuronal dysfunction induced by Parkinson’s patient brain-derived α-synuclein. J Neurosci Res. 2021;99(4):1161–76. https://doi.org/10.1002/jnr.24782.
Gold WA, Krishnarajy R, Ellaway C, Christodoulou J. Rett syndrome: a genetic update and clinical review focusing on comorbidities. ACS Chem Neurosci. 2018;9(2):167–76. https://doi.org/10.1021/acschemneuro.7b00346.
Vidal S, Xiol C, Pascual-Alonso A, O’Callaghan M, Pineda M, Armstrong J. Genetic landscape of Rett syndrome spectrum: improvements and challenges. Int J Mol Sci. 2019;20(16):3925. https://doi.org/10.3390/ijms20163925.
Chahrour M, Jung SY, Shaw C, Zhou X, Wong ST, Qin J, et al. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science. 2008;320(5880):1224–9. https://doi.org/10.1126/science.1153252.
Lyst MJ, Bird A. Rett syndrome: a complex disorder with simple roots. Nat Rev Genet. 2015;16(5):261–75. https://doi.org/10.1038/nrg3897.
Kriaucionis S, Paterson A, Curtis J, Guy J, Macleod N, Bird A. Gene expression analysis exposes mitochondrial abnormalities in a mouse model of Rett syndrome. Mol Cell Biol. 2006;26(13):5033–42. https://doi.org/10.1128/mcb.01665-05.
Ricciardi S, Boggio EM, Grosso S, Lonetti G, Forlani G, Stefanelli G, et al. Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model. Hum Mol Genet. 2011;20(6):1182–96. https://doi.org/10.1093/hmg/ddq563.
Palmer A, Qayumi J, Ronnett G. MeCP2 mutation causes distinguishable phases of acute and chronic defects in synaptogenesis and maintenance, respectively. Mol Cell Neurosci. 2008;37(4):794–807. https://doi.org/10.1016/j.mcn.2008.01.005.
Fonzo M, Sirico F, Corrado B. Evidence-based physical therapy for individuals with Rett syndrome: a systematic review. Brain Sci. 2020;10(7):410. https://doi.org/10.3390/brainsci10070410.
Ehinger Y, Matagne V, Villard L, Roux JC. Rett syndrome from bench to bedside: recent advances. F1000Res. 2018;7:398. https://doi.org/10.12688/f1000research.14056.1.
Chahil G, Bollu PC. Rett Syndrome. In: Aboubakr S, Abu-Ghosh A, Acharya A, Adibi Sedeh P, Aeby T, Aeddula N, Et al. Editors. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. 2023. https://www.ncbi.nlm.nih.gov/books/NBK482252/.
Ohno K, Saito Y, Ueda R, Togawa M, Ohmae T, Matsuda E, et al. Effect of serotonin 1A agonists and selective serotonin reuptake inhibitors on behavioral and nighttime respiratory symptoms in Rett syndrome. Pediatr Neurol. 2016;60:54-9.e1. https://doi.org/10.1016/j.pediatrneurol.2016.03.016.
Neul JL, Lane JB, Lee H-S, Geerts S, Barrish JO, Annese F, et al. Developmental delay in Rett syndrome: data from the natural history study. J Neurodev Disord. 2014;6(1):20. https://doi.org/10.1186/1866-1955-6-20.
Luikenhuis S, Giacometti E, Beard CF, Jaenisch R. Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice. Proc Natl Acad Sci USA. 2004;101(16):6033–8. https://doi.org/10.1073/pnas.0401626101.
Cohen DR, Matarazzo V, Palmer AM, Tu Y, Jeon O-H, Pevsner J, et al. Expression of MeCP2 in olfactory receptor neurons is developmentally regulated and occurs before synaptogenesis. Mol Cell Neurosci. 2003;22(4):417–29. https://doi.org/10.1016/s1044-7431(03)00026-5.
Chen WG, Chang Q, Lin Y, Meissner A, West AE, Griffith EC, et al. Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science. 2003;302(5646):885–9. https://doi.org/10.1126/science.1086446.
Kikuchi-Utsumi K, Nakaki T. Chronic treatment with a selective ligand for the sigma-1 receptor chaperone, SA4503, up-regulates BDNF protein levels in the rat hippocampus. Neurosci Lett. 2008;440(1):19–22. https://doi.org/10.1016/j.neulet.2008.05.055.
Mysona BA, Zhao J, Smith S, Bollinger KE. Relationship between Sigma-1 receptor and BDNF in the visual system. Exp Eye Res. 2018;167:25–30. https://doi.org/10.1016/j.exer.2017.10.012.
Hashimoto K. Sigma-1 receptor chaperone and brain-derived neurotrophic factor: emerging links between cardiovascular disease and depression. Prog Neurobiol. 2013;100:15–29. https://doi.org/10.1016/j.pneurobio.2012.09.001.
Nakano M, Osada K, Misonoo A, Fujiwara K, Takahashi M, Ogawa Y, et al. Fluvoxamine and sigma-1 receptor agonists dehydroepiandrosterone (DHEA)-sulfate induces the Ser473-phosphorylation of Akt-1 in PC12 cells. Life Sci. 2010;86(9–10):309–14. https://doi.org/10.1016/j.lfs.2009.11.017.
Christ MG, Clement AM, Behl C. The sigma-1 receptor at the crossroad of proteostasis, neurodegeneration, and autophagy. Trends Neurosci. 2020;43(2):79–81. https://doi.org/10.1016/j.tins.2019.12.002.
Urano F. Wolfram syndrome: diagnosis, management, and treatment. Curr Diab Rep. 2016;16(1):6. https://doi.org/10.1007/s11892-015-0702-6.
Abreu D, Urano F. Current landscape of treatments for Wolfram syndrome. Trends Pharmacol Sci. 2019;40(10):711–4. https://doi.org/10.1016/j.tips.2019.07.011.
Delprat B, Maurice T, Delettre C. Wolfram syndrome: MAMs’ connection? Cell Death Dis. 2018;9(3):364. https://doi.org/10.1038/s41419-018-0406-3.
Mori T, Hayashi T, Hayashi E, Su TP. Sigma-1 receptor chaperone at the ER-mitochondrion interface mediates the mitochondrion-ER-nucleus signaling for cellular survival. PLoS ONE. 2013;8(10):e76941. https://doi.org/10.1371/journal.pone.0076941.
Crouzier L, Danese A, Yasui Y, Richard EM, Liévens J-C, Patergnani S, et al. Activation of the sigma-1 receptor chaperone alleviates symptoms of Wolfram syndrome in preclinical models. Sci Transl Med. 2022;14(631):eabh3763. https://doi.org/10.1126/scitranslmed.abh3763.
Kornhuber J, Bormann J, Hübers M, Rusche K, Riederer P. Effects of the 1-amino-adamantanes at the MK-801-binding site of the NMDA-receptor-gated ion channel: a human postmortem brain study. Eur J Pharmacol. 1991;206(4):297–300. https://doi.org/10.1016/0922-4106(91)90113-v.
Blanpied TA, Clarke RJ, Johnson JW. Amantadine inhibits NMDA receptors by accelerating channel closure during channel block. J Neurosci. 2005;25(13):3312–22. https://doi.org/10.1523/jneurosci.4262-04.2005.
Peeters M, Romieu P, Maurice T, Su TP, Maloteaux JM, Hermans E. Involvement of the sigma1 receptor in the modulation of dopaminergic transmission by amantadine. Eur J Neurosci. 2004;19(8):2212–20. https://doi.org/10.1111/j.0953-816X.2004.03297.x.
Abbas H. Expression of sigma receptors in human cancer cell lines and effects of novel sigma-2 ligands on their proliferation [Doctoral Thesis]. In. The University of Wolverhampton open repository. 2018. http://hdl.handle.net/2436/621768. Accessed 1 Dec 2022.
Hubsher G, Haider M, Okun MS. Amantadine: the journey from fighting flu to treating Parkinson disease. Neurology. 2012;78(14):1096–9. https://doi.org/10.1212/WNL.0b013e31824e8f0d.
Chang C, Ramphul K. Amantadine. In: Aboubakr S, Abu-Ghosh A, Acharya A, Adibi Sedeh P, Aeby T, Aeddula N, et al. Editors. StatPearls. Treasure Island (FL): StatPearls Publishing. 2023. https://www.ncbi.nlm.nih.gov/books/NBK499953/.
Schwab RS, England AC, Poskanzer DC, Young RR. Amantadine in the treatment of Parkinson’s disease. JAMA. 1969;208(7):1168–70.
Rascol O, Fabbri M, Poewe W. Amantadine in the treatment of Parkinson’s disease and other movement disorders. Lancet Neurol. 2021;20(12):1048–56. https://doi.org/10.1016/S1474-4422(21)00249-0.
Kornhuber J, Schoppmeyer K, Riederer P. Affinity of 1-aminoadamantanes for the σ binding site in post-mortem human frontal cortex. Neurosci Lett. 1993;163(2):129–31. https://doi.org/10.1016/0304-3940(93)90362-O.
Crosby NJ, Deane KH, Clarke CE. Amantadine for dyskinesia in Parkinson’s disease. Cochrane Database Syst Rev. 2003;2003(2):CD003467. https://doi.org/10.1002/14651858.Cd003467.
Aoki FY, Sitar DS. Clinical pharmacokinetics of amantadine hydrochloride. Clin Pharmacokinet. 1988;14(1):35–51. https://doi.org/10.2165/00003088-198814010-00003.
Al-Salama ZT. Amantadine extended release capsules (GOCOVRI) in Parkinson’s disease: a profile of its use in the USA. Drugs Ther Perspect. 2022;38(5):203–14. https://doi.org/10.1007/s40267-022-00912-y.
Hauser RA, Mehta SH, Kremens D, et al. Effects of Gocovri (amantadine) extended-release capsules on motor aspects of experiences of daily living in people with Parkinson’s disease and dyskinesia. Neurol Ther. 2021;10(2):739–51. https://doi.org/10.1007/s40120-021-00256-1.
Elmer LW, Juncos JL, Singer C, et al. Pooled analyses of phase III studies of ADS-5102 (amantadine) extended-release capsules for dyskinesia in Parkinson’s disease. CNS Drugs. 2018;32:387–98. https://doi.org/10.1007/s40263-018-0498-4.
Isaacson SH, Fahn S, Pahwa R, et al. Parkinson’s patients with dyskinesia switched from immediate release amantadine to open-label ADS-5102. Mov Disord Clin Pract. 2018;5:183–90. https://doi.org/10.1002/mdc3.12595.
Oertel W, Eggert K, Pahwa R, Tanner CM, Hauser RA, Trenkwalder C, et al. Randomized, placebo-controlled trial of ADS-5102 (amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson’s disease (EASE LID 3). Mov Disord. 2017;32(12):1701–9. https://doi.org/10.1002/mds.27131.
Pahwa R, Tanner CM, Hauser RA, Isaacson SH, Nausieda PA, Truong DD, et al. ADS-5102 (amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson disease (EASE LID study): a randomized clinical trial. JAMA Neurol. 2017;74(8):941–9. https://doi.org/10.1001/jamaneurol.2017.0943.
Tanner CM, Pahwa R, Hauser RA, Oertel WH, Isaacson SH, Jankovic J, et al. EASE LID 2: a 2-year open-label trial of gocovri (amantadine) extended release for dyskinesia in Parkinson’s disease. J Parkinsons Dis. 2020;10(2):543–58. https://doi.org/10.3233/JPD-191841.
Rosenberg GA, Appenzeller O. Amantadine, fatigue, and multiple sclerosis. Arch Neurol. 1988;45(10):1104–6. https://doi.org/10.1001/archneur.1988.00520340058012.
Shaygannejad V, Janghorbani M, Ashtari F, Zakeri H. Comparison of the effect of aspirin and amantadine for the treatment of fatigue in multiple sclerosis: a randomized, blinded, crossover study. Neurol Res. 2012;34(9):854–8. https://doi.org/10.1179/1743132812Y.0000000081.
Ledinek AH, Sajko MC, Rot U. Evaluating the effects of amantadin, modafinil and acetyl-L-carnitine on fatigue in multiple sclerosis–result of a pilot randomized, blind study. Clin Neurol Neurosurg. 2013;115:S86–9. https://doi.org/10.1016/j.clineuro.2013.09.029.
Khazaei M, Karevan A, Taheri M, Ghafouri-Fard S. Comparison of the effects of amantadine and ondansetron in treatment of fatigue in patients with multiple sclerosis. Clin Transl Med. 2019;8(1):20. https://doi.org/10.1186/s40169-019-0239-4.
Puca F, Bricolo A, Turella G. Effect of L-dopa or amantadine therapy on sleep spindles in Parkinsonism. Electroencephalogr Clin Neurophysiol. 1973;35(3):327–30. https://doi.org/10.1016/0013-4694(73)90245-9.
Nourbakhsh B, Revirajan N, Morris B, Cordano C, Creasman J, Manguinao M, et al. Safety and efficacy of amantadine, modafinil, and methylphenidate for fatigue in multiple sclerosis: a randomised, placebo-controlled, crossover, double-blind trial. Lancet Neurol. 2021;20(1):38–48. https://doi.org/10.1016/s1474-4422(20)30354-9.
Villard V, Espallergues J, Keller E, Vamvakides A, Maurice T. Anti-amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigma1 (σ1) ligand ANAVEX2-73, a novel aminotetrahydrofuran derivative. J Psychopharmacol. 2011;25(8):1101–17. https://doi.org/10.1177/0269881110379286.
Lahmy V, Meunier J, Malmström S, Naert G, Givalois L, Kim SH, et al. Blockade of Tau hyperphosphorylation and Aβ 1–42 generation by the aminotetrahydrofuran derivative ANAVEX2-73, a mixed muscarinic and σ 1 receptor agonist, in a nontransgenic mouse model of Alzheimer’s disease. Neuropsychopharmacology. 2013;38(9):1706. https://doi.org/10.1038/npp.2013.70.
Lahmy V, Long R, Morin D, Villard V, Maurice T. Mitochondrial protection by the mixed muscarinic/σ1 ligand ANAVEX2-73, a tetrahydrofuran derivative, in Aβ25–35 peptide-injected mice, a nontransgenic Alzheimer’s disease model. Front Cell Neurosci. 2015;8:463. https://doi.org/10.3389/fncel.2014.00463.
Voges O, Weigmann I, Bitterlich N, Missling C, Schindler C. A Phase I dose escalation study to investigate safety, tolerability, and pharmacokinetics of ANAVEX 2‐73 in Healthy Male Subjects. Innov Clin Neurosci. 2014;12(Suppl B), 1-20; CNS Summit 2014, Boca Raton, Florida.
Hampel H, Williams C, Etcheto A, Goodsaid F, Parmentier F, Sallantin J, et al. A precision medicine framework using artificial intelligence for the identification and confirmation of genomic biomarkers of response to an Alzheimer’s disease therapy: Analysis of the blarcamesine (ANAVEX2-73) Phase 2a clinical study. Alzheimers Dement. 2020;6(1):e12013. https://doi.org/10.1002/trc2.12013.
Lisak RP, Nedelkoska L, Benjamins JA. Sigma-1 receptor agonists as potential protective therapies in multiple sclerosis. J Neuroimmunol. 2020;342:577188. https://doi.org/10.1016/j.jneuroim.2020.577188.
Kaufmann WE, Sprouse J, Rebowe N, Hanania T, Klamer D, Missling CU. ANAVEX 2–73 (blarcamesine), a Sigma-1 receptor agonist, ameliorates neurologic impairments in a mouse model of Rett syndrome. Pharmacol Biochem Behav. 2019;187:172796. https://doi.org/10.1016/j.pbb.2019.172796.
Reyes ST, Deacon RM, Guo SG, Altimiras FJ, Castillo JB, van der Wildt B, et al. Effects of the sigma-1 receptor agonist blarcamesine in a murine model of fragile X syndrome: neurobehavioral phenotypes and receptor occupancy. Sci Rep. 2021;11(1):17150. https://doi.org/10.1038/s41598-021-94079-7.
Anavex-Life-Sciences-Corp. ANAVEX2-73 (Blarcamesine) AVATAR phase 3 trial met primary and secondary efficacy endpoints. In: Anavex press release. 2022. https://www.anavex.com/post/anavex-2-73-blarcamesine-avatar-phase-3-trial-met-primary-and-secondary-efficacy-endpoints. Accessed 1 Nov 2022.
Hall H, Iulita MF, Gubert P, Flores Aguilar L, Ducatenzeiler A, Fisher A, et al. AF710B, an M1/sigma-1 receptor agonist with long-lasting disease-modifying properties in a transgenic rat model of Alzheimer’s disease. Alzheimers Dement. 2018;14(6):811–23. https://doi.org/10.1016/j.jalz.2017.11.009.
Anavex-life-Sciences-Corp. Anavex Life Sciences reports positive results from phase 1 clinical trial of ANAVEX3-71. In: Anavex press release. 2022. https://www.anavex.com/post/anavex-life-sciences-reports-positive-results-from-phase-1-clinical-trial-of-anavex-3-71. Accessed 1 Nov 2022.
Rishton GM, Look GC, Ni ZJ, Zhang J, Wang Y, Huang Y, et al. Discovery of investigational drug CT1812, an antagonist of the Sigma-2 receptor complex for Alzheimer’s disease. ACS Med Chem Lett. 2021;12(9):1389–95. https://doi.org/10.1021/acsmedchemlett.1c00048.
Izzo NJ, Xu J, Zeng C, Kirk MJ, Mozzoni K, Silky C, et al. Alzheimer’s therapeutics targeting amyloid beta 1–42 oligomers II: sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity. PLoS ONE. 2014;9(11):e111899. https://doi.org/10.1371/journal.pone.0111899.
Izzo NJ, Yuede CM, LaBarbera KM, Limegrover CS, Rehak C, Yurko R, et al. Preclinical and clinical biomarker studies of CT1812: a novel approach to Alzheimer’s disease modification. Alzheimers Dement. 2021;17(8):1365–82. https://doi.org/10.1371/journal.pone.0111899.
Harper AR, Nayee S, Topol EJ. Protective alleles and modifier variants in human health and disease. Nat Rev Genet. 2015;16(12):689–701. https://doi.org/10.1038/nrg4017.
Grundman M, Morgan R, Lickliter JD, Schneider LS, DeKosky S, Izzo NJ, et al. A phase 1 clinical trial of the sigma-2 receptor complex allosteric antagonist CT1812, a novel therapeutic candidate for Alzheimer’s disease. Alzheimers Dement. 2019;5:20–6. https://doi.org/10.1016/j.trci.2018.11.001.
Catalano S, Grundman M, Schneider LS, DeKosky S, Morgan R, Guttendorf R, et al. [P4–567]: a phase 1 safety trial of the Aβ oligomer receptor antagonist CT1812. Alzheimers Dement. 2017;13(7S):P1523–80. https://doi.org/10.1016/j.jalz.2017.07.730.
Schwartz AR, Pizon AF, Brooks DE. Dextromethorphan-induced serotonin syndrome. Clin Toxicol. 2008;46(8):771–3. https://doi.org/10.1080/15563650701668625.
Shin EJ, Nah SY, Chae JS, Bing G, Shin SW, Yen TP, et al. Dextromethorphan attenuates trimethyltin-induced neurotoxicity via sigma1 receptor activation in rats. Neurochem Int. 2007;50(6):791–9. https://doi.org/10.1016/j.neuint.2007.01.008.
Nguyen L, Thomas KL, Lucke-Wold BP, Cavendish JZ, Crowe MS, Matsumoto RR. Dextromethorphan: an update on its utility for neurological and neuropsychiatric disorders. Pharmacol Ther. 2016;159:1–22. https://doi.org/10.1016/j.pharmthera.2016.01.016.
Sauvé WM. Recognizing and treating pseudobulbar affect. CNS Spectr. 2016;21(S1):34–44. https://doi.org/10.1017/S1092852916000791.
Garnock-Jones KP. Dextromethorphan/quinidine. CNS Drugs. 2011;25(5):435–45. https://doi.org/10.2165/11207260-000000000-00000.
Cummings JL, Lyketsos CG, Peskind ER, Porsteinsson AP, Mintzer JE, Scharre DW, et al. Effect of dextromethorphan-quinidine on agitation in patients with Alzheimer disease dementia: a randomized clinical trial. JAMA. 2015;314(12):1242–54. https://doi.org/10.1001/jama.2015.10214.
Senanarong V, Cummings J, Fairbanks L, Mega M, Masterman D, O’connor S, et al. Agitation in Alzheimer’s disease is a manifestation of frontal lobe dysfunction. Dement Geriatr Cogn Disord. 2004;17(1–2):14–20. https://doi.org/10.1159/000074080.
O’Gorman C, Jones A, Cummings JL, et al. Efficacy and safety of AXS‐05, a novel, oral, NMDA‐receptor antagonist with multimodal activity, in agitation associated with Alzheimer’s disease: results from ADVANCE‐1, a phase 2/3, double‐blind, active and placebo‐controlled trial: developments in clinical trials and cognitive assessment. Alzheimer Dement. 2020;16:e047684. https://doi.org/10.1002/alz.047684.
Chou Y-C, Liao J-F, Chang W-Y, Lin M-F, Chen C-F. Binding of dimemorfan to sigma-1 receptor and its anticonvulsant and locomotor effects in mice, compared with dextromethorphan and dextrorphan. Brain Res. 1999;821(2):516–9. https://doi.org/10.1016/s0006-8993(99)01125-7.
Verhagen Metman L, Del Dotto P, Natté R, van den Munckhof P, Chase TN. Dextromethorphan improves levodopa-induced dyskinesias in Parkinson’s disease. Neurology. 1998;51(1):203–6. https://doi.org/10.1212/wnl.51.1.203.
Starr MS, Starr BS, Kaur S. Stimulation of basal and L-DOPA-induced motor activity by glutamate antagonists in animal models of Parkinson’s disease. Neurosci Biobehav Rev. 1997;21(4):437–46. https://doi.org/10.1016/s0149-7634(96)00039-5.
Paquette MA, Brudney EG, Putterman DB, Meshul CK, Johnson SW, Berger SP. Sigma ligands, but not N-methyl-D-aspartate antagonists, reduce levodopa-induced dyskinesias. NeuroReport. 2008;19(1):111–5. https://doi.org/10.1097/WNR.0b013e3282f3b0d1.
Liu C-T, Kao L-T, Shih J-H, Chien W-C, Chiu C-H, Ma K-H, et al. The effect of dextromethorphan use in Parkinson’s disease: a 6-hydroxydopamine rat model and population-based study. Eur J Pharmacol. 2019;862:172639. https://doi.org/10.1016/j.ejphar.2019.172639.
Fox SH, Metman LV, Nutt JG, Brodsky M, Factor SA, Lang AE, et al. Trial of dextromethorphan/quinidine to treat levodopa-induced dyskinesia in Parkinson’s disease. Mov Disord. 2017;32(6):893–903. https://doi.org/10.1002/mds.26976.
Verhagen Metman L, Blanchet PJ, van den Munckhof P, Del Dotto P, Natté R, Chase TN. A trial of dextromethorphan in parkinsonian patients with motor response complications. Mov Disord. 1998;13(3):414–7. https://doi.org/10.1002/mds.870130307.
Wilhelm R, Ahl B, Anghelescu I-G. Dextrometorphan-paroxetine, but not dronabinol, effective for treatment-resistant aggression and agitation in an elderly patient with Lewy body dementia. J Clin Psychopharmacol. 2017;37(6):745–7. https://doi.org/10.1097/jcp.0000000000000805.
Logan BK, Yeakel JK, Goldfogel G, Frost MP, Sandstrom G, Wickham DJ. Dextromethorphan abuse leading to assault, suicide, or homicide. J Forensic Sci. 2012;57(5):1388–94. https://doi.org/10.1111/j.1556-4029.2012.02133.x.
Smith R, Pioro E, Myers K, Sirdofsky M, Goslin K, Meekins G, et al. Enhanced bulbar function in amyotrophic lateral sclerosis: the Nuedexta treatment trial. Neurotherapeutics. 2017;14(3):762–72. https://doi.org/10.1007/s13311-016-0508-5.
Green JR, Allison KM, Cordella C, Richburg BD, Pattee GL, Berry JD, et al. Additional evidence for a therapeutic effect of dextromethorphan/quinidine on bulbar motor function in patients with amyotrophic lateral sclerosis: a quantitative speech analysis. Br J Clin Pharmacol. 2018;84(12):2849–56. https://doi.org/10.1111/bcp.13745.
Sancho J, Ferrer S, Burés E, Díaz JL, Torrecilla T, Signes-Costa J, et al. Effect of one-year dextromethorphan/quinidine treatment on management of respiratory impairment in amyotrophic lateral sclerosis. Respir Med. 2021;186:106536. https://doi.org/10.1016/j.rmed.2021.106536.
Chechneva OV, Mayrhofer F, Daugherty DJ, Pleasure DE, Hong J-S, Deng W. Low dose dextromethorphan attenuates moderate experimental autoimmune encephalomyelitis by inhibiting NOX2 and reducing peripheral immune cells infiltration in the spinal cord. Neurobiol Dis. 2011;44(1):63–72. https://doi.org/10.1016/j.nbd.2011.06.004.
Lisak RP, Nedelkoska L, Benjamins JA. Effects of dextromethorphan on glial cell function: proliferation, maturation, and protection from cytotoxic molecules. Glia. 2014;62(5):751–62. https://doi.org/10.1002/glia.22639.
Pioro EP, Brooks BR, Cummings J, Schiffer R, Thisted RA, Wynn D, et al. Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect. Ann Neurol. 2010;68(5):693–702. https://doi.org/10.1002/ana.22093.
McGrane I, VandenBerg A, Munjal R. Treatment of pseudobulbar affect with fluoxetine and dextromethorphan in a woman with multiple sclerosis. Ann Pharmacother. 2017;51(11):1035–6. https://doi.org/10.1177/1060028017720746.
Ehde DM, Osborne TL, Jensen MP. Chronic pain in persons with multiple sclerosis. Phys Med Rehabil Clin N Am. 2005;16(2):503–12. https://doi.org/10.1016/j.pmr.2005.01.001.
Merlos M, Romero L, Zamanillo D, Plata-Salamán C, Vela JM. Sigma-1 receptor and pain. Handb Exp Pharmacol. 2017;244:131–61. https://doi.org/10.1007/164_2017_9.
Panitch HS, Thisted RA, Smith RA, Wynn DR, Wymer JP, Achiron A, et al. Randomized, controlled trial of dextromethorphan/quinidine for pseudobulbar affect in multiple sclerosis. Ann Neurol. 2006;59(5):780–7. https://doi.org/10.1002/ana.20828.
Nelson KA, Park KM, Robinovitz E, Tsigos C, Max MB. High-dose oral dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia. Neurology. 1997;48(5):1212–8. https://doi.org/10.1212/wnl.48.5.1212.
Abraham RB, Marouani N, Kollender Y, Meller I, Weinbroum AA. Dextromethorphan for phantom pain attenuation in cancer amputees: a double-blind crossover trial involving three patients. Clin J Pain. 2002;18(5):282–5. https://doi.org/10.1097/00002508-200209000-00002.
Carlsson K, Hoem N, Moberg E, Mathisen L. Analgesic effect of dextromethorphan in neuropathic pain. Acta Anaesthesiol Scand. 2004;48(3):328–36. https://doi.org/10.1111/j.0001-5172.2004.0325.x.
Gilron I, Booher S, Rowan J, Smoller B, Max M. A randomized, controlled trial of high-dose dextromethorphan in facial neuralgias. Neurology. 2000;55(7):964–71. https://doi.org/10.1212/wnl.55.7.964.
McQuay HJ, Carroll D, Jadad AR, Glynn CJ, Jack T, Moore RA, et al. Dextromethorphan for the treatment of neuropathic pain: a double-blind randomised controlled crossover trial with integral n-of-1 design. Pain. 1994;59(1):127–33. https://doi.org/10.1016/0304-3959(94)90056-6.
Smith-Hicks CL, Gupta S, Ewen JB, Hong M, Kratz L, Kelley R, Tierney E, Vaurio R, Bibat G, Sanyal A, Yenokyan G, Brereton N, Johnston MV, Naidu S. Randomized open-label trial of dextromethorphan in Rett syndrome. Neurology. 2017;89(16):1684–90. https://doi.org/10.1212/WNL.0000000000004515.
Kumagai K, Shono K, Nakayama H, Ohno Y, Sajai I. (2R-trans)-2-butyl-5-heptylpyrrolidine as a potent sigma receptor ligand produced by Streptomyces longispororuber. Journal Antibiot. 2000;53(5):467–73. https://doi.org/10.7164/antibiotics.53.467.
Moebius FF, Reiter RJ, Hanner M, Glossmann H. High affinity of sigma1-binding sites for sterol isomerization inhibitors: evidence for a pharmacological relationship with the yeast sterol C8–C7 isomerase. Br J Pharmacol. 1997;121(1):1–6. https://doi.org/10.1038/sj.bjp.0701079.
Ramachandran S, Chu UB, Mavlyutov TA, Pal A, Pyne S, Ruoho AE. The sigma1 receptor interacts with N-alkyl amines and endogenous sphingolipids. Eur J Pharmacol. 2009;609(1–3):19–26. https://doi.org/10.1016/j.ejphar.2009.03.003.
Li J, Satyshur K, Guo LW, Ruoho AE. Sphingoid bases regulate the Sigma-1 receptor—sphingosine and N,N’-dimethylsphingosine are endogenous agonists. Int J Mol Sci. 24(4):3103; Doi: https://doi.org/10.3390/ijms24043103
National-Institute-for-Health-and-Care-Excellence. Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer’s disease. In: National Institute for Heath Care Excelence. 2011;TA217:1-77; https://www.nice.org.uk/guidance/ta217. Accessed 1 Nov 2022.
Kato K, Hayako H, Ishihara Y, Marui S, Iwane M, Miyamoto M. TAK-147, an acetylcholinesterase inhibitor, increases choline acetyltransferase activity in cultured rat septal cholinergic neurons. Neurosci Lett. 1999;260(1):5–8. https://doi.org/10.1016/S0304-3940(98)00943-4.
Ramakrishnan NK, Visser AK, Schepers M, Luurtsema G, Nyakas CJ, Elsinga PH, et al. Dose-dependent sigma-1 receptor occupancy by donepezil in rat brain can be assessed with 11 C-SA4503 and microPET. Psychopharmacology. 2014;231(20):3997–4006. https://doi.org/10.1007/s00213-014-3533-2.
Sato K, Urbano R, Yu C, Yamasaki F, Sato T, Jordan J, et al. The effect of donepezil treatment on cardiovascular mortality. Clin Pharmacol Ther. 2010;88(3):335–8. https://doi.org/10.1038/clpt.2010.98.
Nordström P, Religa D, Wimo A, Winblad B, Eriksdotter M. The use of cholinesterase inhibitors and the risk of myocardial infarction and death: a nationwide cohort study in subjects with Alzheimer’s disease. Eur Heart J. 2013;34(33):2585–91. https://doi.org/10.1093/eurheartj/eht182.
Bhuiyan MS, Fukunaga K. Targeting sigma-1 receptor signaling by endogenous ligands for cardioprotection. Expert Opin Ther Targets. 2011;15(2):145–55. https://doi.org/10.1517/14728222.2011.546350.
Ishima T, Nishimura T, Iyo M, Hashimoto K. Potentiation of nerve growth factor-induced neurite outgrowth in PC12 cells by donepezil: role of sigma-1 receptors and IP3 receptors. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(7):1656–9. https://doi.org/10.1016/j.pnpbp.2008.06.011.
Zhang X, Lian S, Zhang Y, Zhao Q. Efficacy and safety of donepezil for mild cognitive impairment: a systematic review and meta-analysis. Clin Neurol Neurosurg. 2022;213:107134. https://doi.org/10.1016/j.clineuro.2022.107134.
Birks JS, Harvey RJ. Donepezil for dementia due to Alzheimer’s disease. Cochrane Database Syst Rev. 2018;6(6):CD001190. https://doi.org/10.1002/14651858.CD001190.pub3.
Wang H, Zong Y, Han Y, Zhao J, Liu H, Liu Y. Compared of efficacy and safety of high-dose donepezil vs standard-dose donepezil among elderly patients with Alzheimer’s disease: a systematic review and meta-analysis. Expert Opin Drug Saf. 2022;21(3):407–15. https://doi.org/10.1080/14740338.2022.2027905.
Howard R, McShane R, Lindesay J, Ritchie C, Baldwin A, Barber R, et al. Donepezil and memantine for moderate-to-severe Alzheimer’s disease. N Engl J Med. 2012;366(10):893–903. https://doi.org/10.1056/NEJMoa1106668.
Tariot PN, Cummings JL, Katz IR, Mintzer J, Perdomo CA, Schwam EM, et al. A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer’s disease in the nursing home setting. J Am Geriatr Soc. 2001;49(12):1590–9.
Ye CY, Lei Y, Tang XC, Zhang HY. Donepezil attenuates Aβ-associated mitochondrial dysfunction and reduces mitochondrial Aβ accumulation in vivo and in vitro. Neuropharmacology. 2015;95:29–36. https://doi.org/10.1016/j.neuropharm.2015.02.020.
Dong H, Yuede CM, Coughlan CA, Murphy KM, Csernansky JG. Effects of donepezil on amyloid-β and synapse density in the Tg2576 mouse model of Alzheimer’s disease. Brain Res. 2009;1303:169–78. https://doi.org/10.1016/j.brainres.2009.09.097.
Ishibashi K, Miura Y, Wagatsuma K, Ishiwata K, Ishii K. Changes in brain amyloid-β accumulation after donepezil administration. J Clin Neurosci. 2017;45:328–9. https://doi.org/10.1016/j.jocn.2017.08.025.
Howard RJ, Juszczak E, Ballard CG, Bentham P, Brown RG, Bullock R, et al. Donepezil for the treatment of agitation in Alzheimer’s disease. N Engl J Med. 2007;357(14):1382–92. https://doi.org/10.1056/NEJMoa066583.
De Keyser J, Sulter G, Luiten PG. Clinical trials with neuroprotective drugs in acute ischaemic stroke: are we doing the right thing? Trends Neurosci. 1999;22(12):535–40. https://doi.org/10.1016/s0166-2236(99)01463-0.
Modell S, Naber D, Holzbach R. Efficacy and safety of an opiate sigma-receptor antagonist (SL 82.0715) in schizophrenic patients with negative symptoms: an open dose-range study. Pharmacopsychiatry. 1996;29(02):63–6. https://doi.org/10.1055/s-2007-979546.
Hashimoto K, London ED. Interactions of erythro-ifenprodil, threo-ifenprodil, erythro-iodoifenprodil, and eliprodil with subtypes of σ receptors. Eur J Pharmacol. 1995;273(3):307–10. https://doi.org/10.1016/0014-2999(94)00763-w.
Brooks S, Kaur S, Starr BS, Starr MS. Motor actions of eliprodil in the normal and monoamine-depleted mouse: a role in the treatment of Parkinson’s disease? J Neural Transm (Vienna). 1996;103(6):737–48. https://doi.org/10.1007/bf01271233.
Demerens C, Stankoff B, Zalc B, Lubetzki C. Eliprodil stimulates CNS myelination: new prospects for multiple sclerosis? Neurology. 1999;52(2):346. https://doi.org/10.1212/wnl.52.2.346.
Silkina I, Gan’shina T, Seredin S, Mirzoian R. Gabaergic mechanism of cerebrovascular and neuroprotective effects of afobazole and picamilon. E Eksp Klin Farmakol. 2005;68(1):20–4.
Antipova T, Sapozhnikova D, Liu B, Seredenin S. Selective anxiolytic afobazole increases the content of BDNF and NGF in cultured hippocampal HT-22 line neurons. Eksp Klin Farmakol. 2009;72(1):12–4.
Cuevas J, Rodriguez A, Behensky A, Katnik C. Afobazole modulates microglial function via activation of both σ-1 and σ-2 receptors. J Pharmacol Exp Ther. 2011;339(1):161–72. https://doi.org/10.1124/jpet.111.182816.
Behensky AA, Yasny IE, Shuster AM, Seredenin SB, Petrov AV, Cuevas J. Stimulation of sigma receptors with afobazole blocks activation of microglia and reduces toxicity caused by amyloid-β25–35. J Pharmacol Exp Ther. 2013;347(2):458–67. https://doi.org/10.1124/jpet.113.208348.
Behensky AA, Yasny IE, Shuster AM, Seredenin SB, Petrov AV, Cuevas J. Afobazole activation of σ-1 receptors modulates neuronal responses to amyloid-β25–35. J Pharmacol Exp Ther. 2013;347(2):468–77. https://doi.org/10.1124/jpet.113.208330.
Martin P, de-Witte PAM, Maurice T, Gammaitoni A, Farfel G, Galer B. Fenfluramine acts as a positive modulator of sigma-1 receptors. Epilepsy Behav. 2020;105:106989. https://doi.org/10.1016/j.yebeh.2020.106989.
Maurice T. Bi-phasic dose response in the preclinical and clinical developments of sigma-1 receptor ligands for the treatment of neurodegenerative disorders. Expert Opin Drug Discov. 2021;16(4):373–89. https://doi.org/10.1080/17460441.2021.1838483.
Knupp KG, Scheffer IE, Ceulemans B, Sullivan JE, Nickels KC, Lagae L, et al. Efficacy and safety of fenfluramine for the treatment of seizures associated with Lennox-Gastaut syndrome: a randomized clinical trial. JAMA Neurol. 2022;79(6):554–64. https://doi.org/10.1001/jamaneurol.2022.0829.
Lagae L, Sullivan J, Knupp K, Laux L, Polster T, Nikanorova M, et al. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet. 2019;394(10216):2243–54. https://doi.org/10.1016/S0140-6736(19)32500-0.
Specchio N, Pietrafusa N, Doccini V, Trivisano M, Darra F, Ragona F, et al. Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a real-world study. Epilepsia. 2020;61(11):2405–14. https://doi.org/10.1111/epi.16690.
Chomchoei C, Brimson J, Brimson S. Repurposing fluoxetine to treat lymphocytic leukaemia: apoptosis induction, sigma-1 receptor upregulation, inhibition of IL-2 cytokine production, and autophagy induction. Expert Opin Ther Targets. 2023. https://doi.org/10.1080/14728222.2022.2166829.
Németh ZK, Szûcs A, Vitrai J, Juhász D, Németh JP, Holló A. Fluoxetine use is associated with improved survival of patients with COVID-19 pneumonia: a retrospective case-control study. Ideggyogy Sz. 2021;74(11–12):389–96. https://doi.org/10.18071/isz.74.0389.
Emilia M, Rosso D, Laura M, María A. Immunomodulatory effects of fluoxetine: a new potential pharmacological action for a classic antidepressant drug ? Pharmacol Res. 2016;109:101–7. https://doi.org/10.1016/j.phrs.2015.11.021.
Safrany ST, Brimson JM. Are fluoxetine’s effects due to sigma-1 receptor agonism? Pharmacol Res. 2016;113:707–8. https://doi.org/10.1016/j.phrs.2016.05.031.
Mostert JP, Admiraal-Behloul F, Hoogduin JM, Luyendijk J, Heersema DJ, Van Buchem MA, et al. Effects of fluoxetine on disease activity in relapsing multiple sclerosis: a double-blind, placebo-controlled, exploratory study. J Neurol Neurosurg Psychiatry. 2008;79(9):1027–31. https://doi.org/10.1136/jnnp.2007.139345.
Lee JY, Kang SR, Yune TY. Fluoxetine prevents oligodendrocyte cell death by inhibiting microglia activation after spinal cord injury. J Neurotrauma. 2015;32(9):633–44. https://doi.org/10.1089/neu.2014.3527.
Sijens PE, Mostert JP, Irwan R, Potze JH, Oudkerk M, De Keyser J. Impact of fluoxetine on the human brain in multiple sclerosis as quantified by proton magnetic resonance spectroscopy and diffusion tensor imaging. Psychiatry Res. 2008;164(3):274–82. https://doi.org/10.1016/j.pscychresns.2007.12.014.
Cambron M, Mostert J, D’Hooghe M, Nagels G, Willekens B, Debruyne J, et al. Fluoxetine in progressive multiple sclerosis: the FLUOX-PMS trial. Mult Scler J. 2019;25(13):1728–35. https://doi.org/10.1177/1352458519843051.
Connick P, De Angelis F, Parker RA, Plantone D, Doshi A, John N, et al. Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART): a multiarm phase IIb randomised, double-blind, placebo-controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis. BMJ Open. 2018;8(8):e021944. https://doi.org/10.1136/bmjopen-2018-021944.
De Angelis F, Connick P, Parker RA, Plantone D, Doshi A, John N, et al. Amiloride, fluoxetine or riluzole to reduce brain volume loss in secondary progressive multiple sclerosis: the MS-SMART four-arm RCT. Efficacy Mech Eval. 2020;7(3):1–72. https://doi.org/10.3310/eme07030.
Chataway J, De Angelis F, Connick P, Parker RA, Plantone D, Doshi A, et al. Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomised placebo-controlled trial. Lancet Neurol. 2020;19(3):214–25. https://doi.org/10.1016/S1474-4422(19)30485-5.
Brimson JM, Prasanth MI, Malar DS, Brimson S, Thitilertdecha P, Tencomnao T. Drugs that offer the potential to reduce hospitalization and mortality from SARS-CoV-2 infection: the possible role of the Sigma-1 receptor and autophagy. Expert Opin Ther Targets. 2021;25(6):35–449. https://doi.org/10.1080/14728222.2021.1952987.
Nishimura T, Ishima T, Iyo M, Hashimoto K. Potentiation of nerve growth factor-induced neurite outgrowth by fluvoxamine: role of sigma-1 receptors, IP3 receptors and cellular signaling pathways. PLoS ONE. 2008;3(7):e2558. https://doi.org/10.1371/journal.pone.0002558.
Benedetti F, Campori E, Colombo C, Smeraldi E. Fluvoxamine treatment of major depression associated with multiple sclerosis. J Neuropsychiatry Clin Neurosci. 2004;16(3):364–6. https://doi.org/10.1176/jnp.16.3.364.
Ghareghani M, Zibara K, Sadeghi H, Dokoohaki S, Sadeghi H, Aryanpour R, et al. Fluvoxamine stimulates oligodendrogenesis of cultured neural stem cells and attenuates inflammation and demyelination in an animal model of multiple sclerosis. Sci Rep. 2017;7(1):4923. https://doi.org/10.1038/s41598-017-04968-z.
Robson MJ, Elliott M, Seminerio MJ, Matsumoto RR. Evaluation of sigma (σ) receptors in the antidepressant-like effects of ketamine in vitro and in vivo. Eur Neuropsychopharmacol. 2012;22(4):308–17. https://doi.org/10.1016/j.euroneuro.2011.08.002.
Nikiforuk A, Popik P. Ketamine prevents stress-induced cognitive inflexibility in rats. Psychoneuroendocrinology. 2014;40:119–22. https://doi.org/10.1016/j.psyneuen.2013.11.009.
Shibakawa YS, Sasaki Y, Goshima Y, Echigo N, Kamiya Y, Kurahashi K, et al. Effects of ketamine and propofol on inflammatory responses of primary glial cell cultures stimulated with lipopolysaccharide. Br J Anaesth. 2005;95(6):803–10. https://doi.org/10.1093/bja/aei256.
Hollinger A, Rüst CA, Riegger H, Gysi B, Tran F, Brügger J, et al. Ketamine vs haloperidol for prevention of cognitive dysfunction and postoperative delirium: a phase IV multicentre randomised placebo-controlled double-blind clinical trial. J Clin Anesth. 2021;68:110099. https://doi.org/10.1016/j.jclinane.2020.110099.
Lara DR, Bisol LW, Munari LR. Antidepressant, mood stabilizing and procognitive effects of very low dose sublingual ketamine in refractory unipolar and bipolar depression. Int J Neuropsychopharmacol. 2013;16(9):2111–7. https://doi.org/10.1017/S1461145713000485.
Zhang MW, Ho RC. Controversies of the effect of ketamine on cognition. Front Psychiatry. 2016;7:47. https://doi.org/10.3389/fpsyt.2016.00047.
Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D. Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry. 2006;63(5):530–8. https://doi.org/10.1001/archpsyc.63.5.530.
Aan Het Rot M, Zarate CA, Charney DS, Mathew SJ. Ketamine for depression: where do we go from here? Biol Psychiatry. 2012;72(7):537–47. https://doi.org/10.1016/j.biopsych.2012.05.003.
Rocha FL, de Vasconcelos Cunha UG, Paschoalin RC, Hara C, Thomaz DP. Use of subcutaneous ketamine to rapidly improve severe treatment-resistant depression in a patient with Alzheimer’s disease. Int Clin Psychopharmacol. 2021;36(2):104–5. https://doi.org/10.1097/YIC.0000000000000334.
He Y, Li H, Huang J, Huang S, Bai Y, Li Y, et al. Efficacy of antidepressant drugs in the treatment of depression in Alzheimer disease patients: a systematic review and network meta-analysis. J Psychopharmacol. 2021;35(8):901–9. https://doi.org/10.1177/02698811211030181.
Yeung L, Wai MS, Fan M, Mak Y, Lam W, Li Z, et al. Hyperphosphorylated tau in the brains of mice and monkeys with long-term administration of ketamine. Toxicol Lett. 2010;193(2):189–93. https://doi.org/10.1016/j.toxlet.2010.01.008.
Ferro M, Angelucci M, Anselmo-Franci J, Canteras N, Da Cunha C. Neuroprotective effect of ketamine/xylazine on two rat models of Parkinson’s disease. Braz J Med Biol Res. 2007;40:89–96. https://doi.org/10.1590/s0100-879x2007000100012.
Vecchia DD, Kanazawa LKS, Wendler E, Hocayen PdAS, Vital MABF, Takahashi RN, et al. Ketamine reversed short-term memory impairment and depressive-like behavior in animal model of Parkinson’s disease. Brain Res Bull. 2021;168:63–73. https://doi.org/10.1016/j.brainresbull.2020.12.011.
Fan J-C, Song J-J, Wang Y, Chen Y, Hong D-X. Neuron-protective effect of subanesthestic-dosage ketamine on mice of Parkinson’s disease. Asian Pac J Trop Med. 2017;10(10):1007–10. https://doi.org/10.1016/j.apjtm.2017.09.014.
Wright JJ, Goodnight PD, McEvoy MD. The utility of ketamine for the preoperative management of a patient with Parkinson’s disease. Anesth Analg. 2009;108(3):980–2. https://doi.org/10.1213/ane.0b013e3181924025.
Salazar G, Motamed C. A remifentanil/ketamine sedation in surgical cancer patients having severe Parkinson’s disease: two case reports. J Opioid Manag. 2012;8(2):133–4. https://doi.org/10.5055/jom.2012.0106.
Barenboim I, Lafer B. Maintenance use of ketamine for treatment-resistant depression: an open-label pilot study. Braz J Psychiatry. 2018;40(1):110. https://doi.org/10.1590/1516-4446-2017-2380.
Mathew SJ, Shah A, Lapidus K, Clark C, Jarun N, Ostermeyer B, et al. Ketamine for treatment-resistant unipolar depression. CNS Drugs. 2012;26(3):189–204. https://doi.org/10.2165/11599770-000000000-00000.
Feifel D. Breaking sad: unleashing the breakthrough potential of k etamine’s rapid antidepressant effects. Drug Dev Res. 2016;77(8):489–94. https://doi.org/10.1002/ddr.21347.
Shiroma PR, Johns B, Kuskowski M, Wels J, Thuras P, Albott CS, et al. Augmentation of response and remission to serial intravenous subanesthetic ketamine in treatment resistant depression. J Affect Disord. 2014;155:123–9. https://doi.org/10.1016/j.jad.2013.10.036.
Wang X, Chang L, Tan Y, Qu Y, Shan J, Hashimoto K. (R)-ketamine ameliorates the progression of experimental autoimmune encephalomyelitis in mice. Brain Res Bull. 2021;177:316–23. https://doi.org/10.1016/j.brainresbull.2021.10.013.
Wang X, Chang L, Wan X, Tan Y, Qu Y, Shan J, et al. (R)-ketamine ameliorates demyelination and facilitates remyelination in cuprizone-treated mice: a role of gut–microbiota–brain axis. Neurobiol Dis. 2022;165:105635. https://doi.org/10.1016/j.nbd.2022.105635.
Sakai T, Tomiyasu S, Ono T, Yamada H, Sumikawa K. Multiple sclerosis with severe pain and allodynia alleviated by oral ketamine. Clin J Pain. 2004;20(5):375–6. https://doi.org/10.1097/00002508-200409000-00016.
Messer MM, Haller IV. Ketamine therapy for treatment-resistant depression in a patient with multiple sclerosis: a case report. Innov Clin Neurosci. 2017;14(1–2):56–9.
Patrizi A, Picard N, Simon AJ, Gunner G, Centofante E, Andrews NA, et al. Chronic administration of the N-methyl-D-aspartate receptor antagonist ketamine improves Rett syndrome phenotype. Biol Psychiatry. 2016;79(9):755–64. https://doi.org/10.1016/j.biopsych.2015.08.018.
Kron M, Howell CJ, Adams IT, Ransbottom M, Christian D, Ogier M, et al. Brain activity mapping in Mecp2 mutant mice reveals functional deficits in forebrain circuits, including key nodes in the default mode network, that are reversed with ketamine treatment. J Neurosci. 2012;32(40):13860–72. https://doi.org/10.1523/jneurosci.2159-12.2012.
Jolly T, McLean HS. Use of ketamine during procedural sedation: indications, controversies, and side effects. J Infus Nurs. 2012;35(6):377–82. https://doi.org/10.1097/NAN.0b013e31827068c1.
Mount C, Downton C. Alzheimer disease: progress or profit? Nat Med. 2006;12(7):780–4. https://doi.org/10.1038/nm0706-780.
Guo J, Wang Z, Liu R, Huang Y, Zhang N, Zhang R. Memantine, donepezil, or combination therapy—what is the best therapy for Alzheimer’s disease? A network meta-analysis. Brain Behav. 2020;10(11):e01831. https://doi.org/10.1002/brb3.1831.
Schmitt HP. On the paradox of ion channel blockade and its benefits in the treatment of Alzheimer disease. Med Hypotheses. 2005;65(2):259–65. https://doi.org/10.1016/j.mehy.2005.03.011.
Parsons C, Danysz W, Quack G. Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist—a review of preclinical data. Neuropharmacol. 1999;38(6):735–67. https://doi.org/10.1016/s0028-3908(99)00019-2.
Rogawski MA, Wenk GL. The neuropharmacological basis for the use of memantine in the treatment of Alzheimer’s disease. CNS Drug Rev. 2003;9(3):275–308. https://doi.org/10.1111/j.1527-3458.2003.tb00254.x.
Martina M, Turcotte MEB, Halman S, Bergeron R. The sigma-1 receptor modulates NMDA receptor synaptic transmission and plasticity via SK channels in rat hippocampus. J Physiol. 2007;578(1):143–57. https://doi.org/10.1113/jphysiol.2006.116178.
Chaki S, Okuyama S, Ogawa S-i, Tomisawa K. Regulation of NMDA-induced [3H] dopamine release from rat hippocampal slices through sigma-1 binding sites. Neurochem Int. 1998;33(1):29–34. https://doi.org/10.1113/jphysiol.2006.116178.
Sha S, Qu WJ, Li L, Lu ZH, Chen L, Yu WF, et al. Sigma-1 receptor knockout impairs neurogenesis in dentate gyrus of adult hippocampus via down-regulation of NMDA receptors. CNS Neurosci Ther. 2013;19(9):705–13. https://doi.org/10.1111/cns.12129.
Pabba M, Wong AY, Ahlskog N, Hristova E, Biscaro D, Nassrallah W, et al. NMDA receptors are upregulated and trafficked to the plasma membrane after sigma-1 receptor activation in the rat hippocampus. J Neurosci. 2014;34(34):11325–38. https://doi.org/10.1523/JNEUROSCI.0458-14.2014.
Stahl SM. Mechanism of action of ketamine. CNS Spectr. 2013;18(4):171–4. https://doi.org/10.1017/S109285291300045X.
Winblad B, Jones RW, Wirth Y, Stöffler A, Möbius HJ. Memantine in moderate to severe Alzheimer’s disease: a meta-analysis of randomised clinical trials. Dement Geriatr Cogn Disord. 2007;24(1):20–7. https://doi.org/10.1159/000102568.
Atri A, Molinuevo JL, Lemming O, Wirth Y, Pulte I, Wilkinson D. Memantine in patients with Alzheimer’s disease receiving donepezil: new analyses of efficacy and safety for combination therapy. Alzheimers Res Ther. 2013;5(1):6. https://doi.org/10.1186/alzrt160.
Schmitt FA, van Dyck CH, Wichems CH, Olin JT, Group MM-M-S. Cognitive response to memantine in moderate to severe Alzheimer disease patients already receiving donepezil: an exploratory reanalysis. Alzheimer Dis Assoc Disord. 2006;20(4):255–62. https://doi.org/10.1097/01.wad.0000213860.35355.d4.
Lopez OL, Becker JT, Wahed AS, Saxton J, Sweet RA, Wolk DA, et al. Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease. J Neurol Neurosurg Psychiatry. 2009;80(6):600–7. https://doi.org/10.1136/jnnp.2008.158964.
Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I, et al. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004;291(3):317–24. https://doi.org/10.1001/jama.291.3.317.
Hendrix S, Ellison N, Stanworth S, Otcheretko V, Tariot PN. Post Hoc Evidence for an additive effect of memantine and donepezil: consistent findings from DOMINO-AD Study and Memantine Clinical Trial Program. J Prev Alzheimers Dis. 2015;2(3):165–71. https://doi.org/10.14283/jpad.2015.66.
Porsteinsson AP, Grossberg GT, Mintzer J, Olin JT. Memantine treatment in patients with mild to moderate Alzheimer’s disease already receiving a cholinesterase inhibitor: a randomized, double-blind, placebo-controlled trial. Curr Alzheimer Res. 2008;5(1):83–9. https://doi.org/10.2174/156720508783884576.
Leroi I, Overshott R, Byrne EJ, Daniel E, Burns A. Randomized controlled trial of memantine in dementia associated with Parkinson’s disease. Mov Disord. 2009;24(8):1217–21. https://doi.org/10.1002/mds.22495.
Emre M, Tsolaki M, Bonuccelli U, Destée A, Tolosa E, Kutzelnigg A, et al. Memantine for patients with Parkinson’s disease dementia or dementia with Lewy bodies: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2010;9(10):969–77. https://doi.org/10.1016/S1474-4422(10)70194-0.
Ondo WG, Shinawi L, Davidson A, et al. Memantine for non-motor features of Parkinson’s disease: a double-blind placebo controlled exploratory pilot trial. Parkinsonism Relat Disord. 2011;17(3):156–9. https://doi.org/10.1016/j.parkreldis.2010.12.003.
Moreau C, Delval A, Tiffreau V, et al. Memantine for axial signs in Parkinson’s disease: a randomised, double-blind, placebo-controlled pilot study. J Neurol Neurosurg Psychiatry. 2013;84(5):552–5. https://doi.org/10.1136/jnnp-2012-303182.
Wang HF, Yu JT, Tang SW, Jiang T, Tan CC, Meng XF, et al. Efficacy and safety of cholinesterase inhibitors and memantine in cognitive impairment in Parkinson’s disease, Parkinson’s disease dementia, and dementia with Lewy bodies: systematic review with meta-analysis and trial sequential analysis. J Neurol Neurosurg Psychiatry. 2015;86(2):135–43. https://doi.org/10.1136/jnnp-2014-307659.
Sanjay M, Amir G, John R, Scott O, Stephen D, et al. Short-term tolerability of a nonazapirone selective serotonin 1A agonist in adults with generalized anxiety disorder: a 28-day, open-label study. Clin Ther. 2008;30:9. https://doi.org/10.1016/j.clinthera.2008.09.006.
Rickels K, Mathew S, Banov MD, Zimbroff DL, Oshana S, Parsons EC Jr, et al. Effects of PRX-00023, a novel, selective serotonin 1A receptor agonist on measures of anxiety and depression in generalized anxiety disorder: results of a double-blind, placebo-controlled trial. J Clin Psychopharmacol. 2008;28(2):235–9. https://doi.org/10.1097/JCP.0b013e31816774de.
PRX-00023 Therapy in localization-related epilepsy. In: NIH U.S. National Library of Medicine clinical trials web site; 2011. https://clinicaltrials.gov/ct2/show/NCT01281956. Accessed 1 Dec 2022.
Merritt HH, Putnam TJ. Sodium diphenyl hydantoinate in the treatment of convulsive disorders. J Am Med Assoc. 1938;111(12):1068–73. https://doi.org/10.1001/jama.1938.02790380010004.
Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci. 2004;5(7):553–64. https://doi.org/10.1038/nrn1430.
Tchedre KT, Huang RQ, Dibas A, Krishnamoorthy RR, Dillon GH, Yorio T. Sigma-1 receptor regulation of voltage-gated calcium channels involves a direct interaction. Invest Ophthalmol Vis Sci. 2008;49(11):4993–5002. https://doi.org/10.1167/iovs.08-1867.
Mueller BH II, Park Y, Daudt DR III, Ma H-Y, Akopova I, Stankowska DL, et al. Sigma-1 receptor stimulation attenuates calcium influx through activated L-type voltage gated calcium channels in purified retinal ganglion cells. Exp Eye Res. 2013;107:21–31. https://doi.org/10.1016/j.exer.2012.11.002.
Zhang K, Zhao Z, Lan L, Wei X, Wang L, Liu X, et al. Sigma-1 receptor plays a negative modulation on N-type calcium channel. Front Pharmacol. 2017;8:302. https://doi.org/10.3389/fphar.2017.00302.
Zhang H, Cuevas J. Sigma receptors inhibit high-voltage–activated calcium channels in rat sympathetic and parasympathetic neurons. J Neurophysiol. 2002;87(6):2867–79. https://doi.org/10.1152/jn.2002.87.6.2867.
DeHaven-Hudkins D, Ford-Rice F, Allen J, Hudkins R. Allosteric modulation of ligand binding to [3H](+) pentazocine-defined σ recognition sites by phenytoin. Life Sci. 1993;53(1):41–8. https://doi.org/10.1016/0024-3205(93)90609-7.
Braakman HM, Verhoeven JS, Erasmus CE, Haaxma CA, Willemsen MH, Schelhaas HJ. Phenytoin as a last-resort treatment in SCN 8A encephalopathy. Epilepsia Open. 2017;2(3):343–4. https://doi.org/10.1002/epi4.12059.
Dilena R, Striano P, Gennaro E, Bassi L, Olivotto S, Tadini L, et al. Efficacy of sodium channel blockers in SCN2A early infantile epileptic encephalopathy. Brain Dev. 2017;39(4):345–8. https://doi.org/10.1016/j.braindev.2016.10.015.
Su TP, Wu XZ, Cone EJ, Shukla K, Gund TM, Dodge AL, et al. Sigma compounds derived from phencyclidine: identification of PRE-084, a new, selective sigma ligand. J Pharmacol Exp Ther. 1991;259(2):543–50.
Motawe ZY, Abdelmaboud SS, Cuevas J, Breslin JW. PRE-084 as a tool to uncover potential therapeutic applications for selective sigma-1 receptor activation. Int J Biochem Cell Biol. 2020;126:105803; Doi: https://doi.org/10.1016/j.biocel.2020.105803
Motawe ZY, Farsaei F, Abdelmaboud SS, Cuevas J, Breslin JW. Sigma-1 receptor activation-induced glycolytic ATP production and endothelial barrier enhancement. Microcirculation. 2020;27(6):e12620. https://doi.org/10.1111/micc.12620.
An Y, Qi Y, Li Y, Li Z, Yang C, Jia D. Activation of the sigma-1 receptor attenuates blood–brain barrier disruption by inhibiting amyloid deposition in Alzheimer’s disease mice. Neurosci Lett. 2022;774:136528. https://doi.org/10.1016/j.neulet.2022.136528.
Penas C, Pascual-Font A, Mancuso R, Forés J, Casas C, Navarro X. Sigma receptor agonist 2-(4-morpholinethyl) 1 phenylcyclohexanecarboxylate (Pre084) increases GDNF and BiP expression and promotes neuroprotection after root avulsion injury. J Neurotrauma. 2011;28(5):831–40. https://doi.org/10.1089/neu.2010.1674.
Francardo V, Bez F, Wieloch T, Nissbrandt H, Ruscher K, Cenci MA. Pharmacological stimulation of sigma-1 receptors has neurorestorative effects in experimental parkinsonism. Brain. 2014;137(7):1998–2014. https://doi.org/10.1093/brain/awu107.
Rao YL, Ganaraja B, Murlimanju BV, Joy T, Krishnamurthy A, Agrawal A. Hippocampus and its involvement in Alzheimer’s disease: a review. 3 Biotech. 2022;12(2):55; Doi: https://doi.org/10.1007/s13205-022-03123-4
Eriksson PS, Perfilieva E, Björk-Eriksson T, Alborn A-M, Nordborg C, Peterson DA, et al. Neurogenesis in the adult human hippocampus. Nat Med. 1998;4(11):1313–7. https://doi.org/10.1038/3305.
Borbély E, Varga V, Szögi T, Schuster I, Bozsó Z, Penke B, et al. Impact of two neuronal Sigma-1 receptor modulators, PRE084 and DMT, on neurogenesis and neuroinflammation in an Aβ1–42-injected, wild-type mouse model of AD. Int J Mol Sci. 2022;23(5):2514. https://doi.org/10.3390/ijms23052514.
Li L, Xu B, Zhu Y, Chen L, Sokabe M, Chen L. DHEA prevents Aβ25–35-impaired survival of newborn neurons in the dentate gyrus through a modulation of PI3K-Akt-mTOR signaling. Neuropharmacol. 2010;59(4–5):323–33. https://doi.org/10.1016/j.neuropharm.2010.02.009.
Estévez-Silva HM, Cuesto G, Romero N, Brito-Armas JM, Acevedo-Arozena A, Acebes Á, et al. Pridopidine promotes synaptogenesis and reduces spatial memory deficits in the Alzheimer’s disease APP/PS1 mouse model. Neurotherapeutics. 2022;19(5):1566–87. https://doi.org/10.1007/s13311-022-01280-1.
Guzmán-Lenis MS, Navarro X, Casas C. Selective sigma receptor agonist 2-(4-morpholinethyl) 1-phenylcyclohexanecarboxylate (PRE084) promotes neuroprotection and neurite elongation through protein kinase C (PKC) signaling on motoneurons. Neuroscience. 2009;162(1):31–8. https://doi.org/10.1016/j.neuroscience.2009.03.067.
Mancuso R, Oliván S, Rando A, Casas C, Osta R, Navarro X. Sigma-1R agonist improves motor function and motoneuron survival in ALS mice. Neurotherapeutics. 2012;9(4):814–26. https://doi.org/10.1007/s13311-012-0140-y.
Mancuso R, Del Valle J, Morell M, Pallás M, Osta R, Navarro X. Lack of synergistic effect of resveratrol and sigma-1 receptor agonist (PRE-084) in SOD1G93A ALS mice: overlapping effects or limited therapeutic opportunity? Orphanet J Rare Dis. 2014;9(1):1–11. https://doi.org/10.1186/1750-1172-9-78.
Gaja-Capdevila N, Hernández N, Navarro X, Herrando-Grabulosa M. Sigma-1 receptor is a pharmacological target to promote neuroprotection in the SOD1G93A ALS mice. Front Pharmacol. 2021;12:780588. https://doi.org/10.3389/fphar.2021.780588.
Peviani M, Salvaneschi E, Bontempi L, Petese A, Manzo A, Rossi D, et al. Neuroprotective effects of the Sigma-1 receptor (S1R) agonist PRE-084, in a mouse model of motor neuron disease not linked to SOD1 mutation. Neurobiol Dis. 2014;62:218–32. https://doi.org/10.1016/j.nbd.2013.10.010.
Barwick SR, Siddiq MS, Wang J, Xiao H, Marshall B, Perry E, et al. Sigma 1 receptor co-localizes with NRF2 in retinal photoreceptor cells. Antioxidants. 2021;10(6):981. https://doi.org/10.3390/antiox10060981.
Weng TY, Hung DT, Su TP, Tsai SYA. Loss of Sigma-1 receptor chaperone promotes astrocytosis and enhances the Nrf2 antioxidant defense. Oxid Med Cell Longev. 2017;2017:4582135. https://doi.org/10.1155/2017/4582135.
Lasbleiz C, Peyrel A, Tarot P, Sarniguet J, Crouzier L, Cubedo N, et al. Sigma-1 receptor agonist PRE-084 confers protection against TAR DNA-binding protein-43 toxicity through NRF2 signalling. Redox Biol. 2022;58:102542. https://doi.org/10.1016/j.redox.2022.102542.
Hyrskyluoto A, Pulli I, Törnqvist K, Ho H, Korhonen L, Lindholm D. Sigma-1 receptor agonist PRE084 is protective against mutant huntingtin-induced cell degeneration: involvement of calpastatin and the NF-κB pathway. Cell Death Dis. 2013;4(5):e646. https://doi.org/10.1038/cddis.2013.170.
Bol’Shakova A, Kraskovskaya N, Gainullina A, Kukanova E, Vlasova O, Bezprozvanny I. Neuroprotective effect of σ1-receptors on the cell model of Huntington’s disease. Bull Exp Biol Med. 2017;164:252–8. https://doi.org/10.1007/s10517-017-3968-7.
Johnston TH, Geva M, Steiner L, Orbach A, Papapetropoulos S, Savola JM, et al. Pridopidine, a clinic-ready compound, reduces 3, 4-dihydroxyphenylalanine-induced dyskinesia in Parkinsonian macaques. Mov Disord. 2019;34(5):708–16. https://doi.org/10.1002/mds.27565.
Grachev ID, Meyer PM, Becker GA, Bronzel M, Marsteller D, Pastino G, et al. Sigma-1 and dopamine D2/D3 receptor occupancy of pridopidine in healthy volunteers and patients with Huntington disease: a [(18)F] fluspidine and [(18)F] fallypride PET study. Eur J Nucl Med Mol Imaging. 2021;48(4):1103–15. https://doi.org/10.1007/s00259-020-05030-3.
Sahlholm K, Sijbesma JWA, Maas B, Kwizera C, Marcellino D, Ramakrishnan NK, et al. Pridopidine selectively occupies sigma-1 rather than dopamine D2 receptors at behaviorally active doses. Psychopharmacology. 2015;232(18):3443–53. https://doi.org/10.1007/s00213-015-3997-8.
Bourne J, Harris KM. Do thin spines learn to be mushroom spines that remember? Curr Opin Neurobiol. 2007;17(3):381–6. https://doi.org/10.1016/j.conb.2007.04.009.
Bourne JN, Harris KM. Balancing structure and function at hippocampal dendritic spines. Annu Rev Neurosci. 2008;31:47–67. https://doi.org/10.1146/annurev.neuro.31.060407.125646.
Hayashi-Takagi A, Yagishita S, Nakamura M, Shirai F, Wu YI, Loshbaugh AL, et al. Labelling and optical erasure of synaptic memory traces in the motor cortex. Nature. 2015;525(7569):333–8. https://doi.org/10.1038/nature15257.
Ionescu A, Gradus T, Altman T, Maimon R, Avraham NS, Geva M, et al. Targeting the sigma-1 receptor via pridopidine ameliorates central features of ALS pathology in a SOD1G93A model. Cell Death Dis. 2019;10(3):210. https://doi.org/10.1038/s41419-019-1451-2.
Estévez-Silva HM, Mediavilla T, Giacobbo BL, Liu X, Sultan FR, Marcellino DJ. Pridopidine modifies disease phenotype in a SOD1 mouse model of amyotrophic lateral sclerosis. Eur J Neurosci. 2022;55(5):1356–72. https://doi.org/10.1111/ejn.15608.
Wang S-M, Wu H-E, Yasui Y, Geva M, Hayden M, Maurice T, et al. Nucleoporin POM121 signals TFEB-mediated autophagy via activation of SIGMAR1/sigma-1 receptor chaperone by pridopidine. Autophagy. 2023;19(1):126–51. https://doi.org/10.1080/15548627.2022.2063003.
Garcia-Miralles M, Geva M, Tan JY, Yusof NABM, Cha Y, Kusko R, et al. Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice. JCI insight. 2017;2:23. https://doi.org/10.1172/jci.insight.95665.
Nguyen KQ, Rymar VV, Sadikot AF. Impaired TrkB signaling underlies reduced BDNF-mediated trophic support of striatal neurons in the R6/2 mouse model of Huntington’s disease. Front Cell Neurosci. 2016;10:37. https://doi.org/10.3389/fncel.2016.00037.
Kusko R, Dreymann J, Ross J, Cha Y, Escalante-Chong R, Garcia-Miralles M, et al. Large-scale transcriptomic analysis reveals that pridopidine reverses aberrant gene expression and activates neuroprotective pathways in the YAC128 HD mouse. Mol Neurodegener. 2018;13(1):25. https://doi.org/10.1186/s13024-018-0259-3.
Xie Y, Hayden MR, Xu B. BDNF overexpression in the forebrain rescues Huntington’s disease phenotypes in YAC128 mice. J Neurosci. 2010;30(44):14708–18. https://doi.org/10.1523/JNEUROSCI.1637-10.2010.
Geva M, Kusko R, Soares H, Fowler KD, Birnberg T, Barash S, et al. Pridopidine activates neuroprotective pathways impaired in Huntington disease. Hum Mol Genet. 2016;25(18):3975–87. https://doi.org/10.1093/hmg/ddw238.
Yagasaki Y, Numakawa T, Kumamaru E, Hayashi T, Su TP, Kunugi H. Chronic antidepressants potentiate via sigma-1 receptors the brain-derived neurotrophic factor-induced signaling for glutamate release. J Biol Chem. 2006;281(18):12941–9. https://doi.org/10.1074/jbc.M508157200.
Huntington Study Group HART Investigators. A randomized, double-blind, placebo-controlled trial of pridopidine in Huntington’s disease. Mov Disord. 2013;28(10):1407–15. https://doi.org/10.1002/mds.25362.
De Yebenes JG, Landwehrmeyer B, Squitieri F, Reilmann R, Rosser A, Barker RA, et al. Pridopidine for the treatment of motor function in patients with Huntington’s disease (MermaiHD): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2011;10(12):1049–57. https://doi.org/10.1016/S1474-4422(11)70233-2.
Reilmann R, McGarry A, Grachev ID, Savola J-M, Borowsky B, Eyal E, et al. Safety and efficacy of pridopidine in patients with Huntington’s disease (PRIDE-HD): a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study. Lancet Neurol. 2019;18(2):165–76. https://doi.org/10.1016/S1474-4422(18)30391-0.
McGarry A, Auinger P, Kieburtz K, Geva M, Mehra M, Abler V, et al. Additional safety and exploratory efficacy data at 48 and 60 months from Open-HART, an open-label extension study of pridopidine in Huntington disease. J Huntingtons Dis. 2020;9(2):173–84. https://doi.org/10.3233/JHD-190393.
Ponten H, Kullingsjö J, Sonesson C, Waters S, Waters N, Tedroff J. The dopaminergic stabilizer pridopidine decreases expression of l-DOPA-induced locomotor sensitisation in the rat unilateral 6-OHDA model. Eur J Pharmacol. 2013;698(1–3):278–85. https://doi.org/10.1016/j.ejphar.2012.10.039.
McFarthing K, Prakash N, Simuni T. Clinical trial highlights – dyskinesia. J Parkinsons Dis. 2019;9:449–65. https://doi.org/10.3233/JPD-199002.
Nadjar A, Gerfen CR, Bezard E. Priming for l-dopa-induced dyskinesia in Parkinson’s disease: a feature inherent to the treatment or the disease? Prog Neurobiol. 2009;87(1):1–9. https://doi.org/10.1016/j.pneurobio.2008.09.013.
Khoury R, Rajamanickam J, Grossberg GT. An update on the safety of current therapies for Alzheimer’s disease: focus on rivastigmine. Ther Adv Drug Saf. 2018;9(3):171–8. https://doi.org/10.1177/2042098617750555.
Terada K, Migita K, Matsushima Y, Sugimoto Y, Kamei C, Matsumoto T, et al. Cholinesterase inhibitor rivastigmine enhances nerve growth factor-induced neurite outgrowth in PC12 cells via sigma-1 and sigma-2 receptors. PLoS ONE. 2018;13(12):e0209250. https://doi.org/10.1371/journal.pone.0209250.
Corey-Bloom J. A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer’s disease. Int J Geriatr Psyopharmacol. 1998;1:55–65.
Rösler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, et al. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial. BMJ. 1999;318(7184):633–8. https://doi.org/10.1136/bmj.318.7184.633.
Finkel SI. Effects of rivastigmine on behavioral and psychological symptoms of dementia in Alzheimer’s disease. Clin Ther. 2004;26(7):980–90. https://doi.org/10.1016/s0149-2918(04)90172-5.
Yi B, Sahn JJ, Ardestani PM, Evans AK, Scott LL, Chan JZ, et al. Small molecule modulator of sigma 2 receptor is neuroprotective and reduces cognitive deficits and neuroinflammation in experimental models of Alzheimer’s disease. J Neurochem. 2017;140(4):561–75. https://doi.org/10.1111/jnc.13917.
Yano T, Tanabe H, Kobayashi K, Kobayashi H, Nabetani A, Sakai Y, et al. Sigma-1 receptor is a molecular target for novel neuroprotectant T-817MA. Alzheimer Dement. 2015;11(7):P861. https://doi.org/10.1016/j.jalz.2015.08.038.
Nguyen PTH, Kimura T, Ho SA, Tran AH, Ono T, Nishijo H. Ameliorative effects of a neuroprotective agent, T-817MA, on place learning deficits induced by continuous infusion of amyloid-β peptide (1–40) in rats. Hippocampus. 2007;17(6):443–55. https://doi.org/10.1002/hipo.20281.
Kimura T, Hong Nguyen PT, Ho SA, Tran AH, Ono T, Nishijo H. T-817MA, a neurotrophic agent, ameliorates the deficits in adult neurogenesis and spatial memory in rats infused icv with amyloid-β peptide. Br J Pharmacol. 2009;157(3):451–63. https://doi.org/10.1111/j.1476-5381.2009.00141.x.
Schneider LS, Thomas RG, Hendrix S, Rissman RA, Brewer JB, Salmon DP, et al. Safety and efficacy of edonerpic maleate for patients with mild to moderate alzheimer disease: a phase 2 randomized clinical trial. JAMA Neurol. 2019;76(11):1330–9. https://doi.org/10.1001/jamaneurol.2019.1868.
Schneider L, Porsteinsson A, Farlow M, Shimakura A, Nakagawa M, Iwakami N. The neuroprotective and neurotrophic agent T-817MA for Alzheimer’s disease: randomized, double-blind, placebo-controlled proof-of-concept trial outcomes. Alzheimers Dement. 2013;9(4):P530–1. https://doi.org/10.1016/j.jalz.2013.04.272.
Audronytė E, Kaubrys G. Odor identification and discrimination as markers of early Alzheimer’s disease. Alzheimers Dement. 2022;18:e063101. https://doi.org/10.1002/alz.063101.
Hudd F, Shiel A, Harris M, Bowdler P, Wood B, Tsivos D, et al. novel blood biomarkers that correlate with cognitive performance and hippocampal volumetry: potential for early diagnosis of Alzheimer’s disease. J Alzheimers Dis. 2019;67(3):931–47. https://doi.org/10.3233/JAD-180879.
Pinto JM, Wroblewski KE, Kern DW, Schumm LP, McClintock MK. Olfactory dysfunction predicts 5-year mortality in older adults. PLoS ONE. 2014;9(10):e107541. https://doi.org/10.1371/journal.pone.0107541.
Adams DR, Kern DW, Wroblewski KE, McClintock MK, Dale W, Pinto JM. Olfactory dysfunction predicts subsequent dementia in older US adults. J Am Geriatr Soc. 2018;66(1):140–4. https://doi.org/10.1111/jgs.15048.
Wang W, Lee J, Harrou F, Sun Y. Early detection of Parkinson’s disease using deep learning and machine learning. IEEE Access. 2020;8:147635–46. https://doi.org/10.1109/ACCESS.2020.3016062.
Lin C-H, Wang F-C, Kuo T-Y, Huang P-W, Chen S-F, Fu L-C. Early detection of Parkinson’s disease by neural network models. IEEE Access. 2022;10:19033–44. https://doi.org/10.1109/ACCESS.2022.3150774.
Acknowledgements
D.S.M. was supported by The Second Century Fund (C2F) for Postdoctoral Fellowship, Chulalongkorn University. The Chulalongkorn University Graduate School Thesis Grant supported K.S.R. All figures were created with www.biorender.com.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
No funding was received for this manuscript.
Conflict of interest
The authors have no conflicts of interest to declare.
Availability of data and material
Data sharing does not apply to this article as no datasets were generated or analysed during the current study.
Ethics approval
Not applicable to this article.
Consent to participate:
Not applicable to this article.
Consent for publication
Not applicable to this article.
Code availability
Not applicable to this article.
Author contributions
Drafting manuscript: JMB, DSM, PT, KSR, SB, TT. Editing Manuscript: JMB, SB. Preparation of Figures: TT, JMB. Literature searching: JMB, PT, KSR, SB, DSM. Manuscript revision: JMB, PT, DSM. All authors have read and approved the final version of the manuscript and agree to be accountable for the work.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Malar, D.S., Thitilertdecha, P., Ruckvongacheep, K.S. et al. Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders. CNS Drugs 37, 399–440 (2023). https://doi.org/10.1007/s40263-023-01007-6
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1007/s40263-023-01007-6
