459
Views
39
CrossRef citations to date
0
Altmetric
Review

Bi-phasic dose response in the preclinical and clinical developments of sigma-1 receptor ligands for the treatment of neurodegenerative disorders

ORCID Icon
Pages 373-389 | Received 03 Jun 2020, Accepted 14 Oct 2020, Published online: 27 Oct 2020

References

  • Corriveau RA, Bosetti F, Emr M, et al. The science of vascular contributions to cognitive impairment and dementia (VCID): a framework for advancing research priorities in the cerebrovascular biology of cognitive decline. Cell Mol Neurobiol. 2016;36:281–288.
  • Selkoe DJ. Cell biology of protein misfolding: the examples of Alzheimer’s and Parkinson’s diseases. Nat Cell Biol. 2004;6:1054–1061.
  • Coleman PD, Mastroeni D. A call for new approaches to Alzheimer’s disease research. Neurobiol Aging. 2017;57:iii–iv.
  • Huang LK, Chao SP, Hu CJ. Clinical trials of new drugs for Alzheimer disease. J Biomed Sci. 2020;27:18.
  • Sveinbjornsdottir S. The clinical symptoms of Parkinson’s disease. J Neurochem. 2016;139(Suppl 1):318–324.
  • Braak H, Ghebremedhin E, Rüb U, et al. Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res. 2004;318:121–134.
  • Logroscino G, Traynor BJ, Hardiman O, et al. Incidence of amyotrophic lateral sclerosis in Europe. J Neurol Neurosurg Psychiatry. 2010;81:385–390.
  • Dharmadasa T, Kiernan MC. Riluzole, disease stage and survival in ALS. Lancet Neurol. 2018;17:385–386.
  • Nagase M, Yamamoto Y, Miyazaki Y, et al. Increased oxidative stress in patients with amyotrophic lateral sclerosis and the effect of edaravone administration. Redox Rep. 2016;21:104–112.
  • Forbes RB, Colville S, Swingler RJ; Scottish ALS/MND Register. The epidemiology of amyotrophic lateral sclerosis (ALS/MND) in people aged 80 or over. Age Ageing. 2004;33:131–134.
  • Dorsey ER, Beck CA, Darwin K, et al. Natural history of Huntington disease. JAMA Neurol. 2013;70:1520–1530.
  • Gil JM, Rego AC. Mechanisms of neurodegeneration in Huntington’s disease. Eur J Neurosci. 2008;27:2803–2820.
  • Reijonen S, Putkonen N, Nørremølle A, et al. Inhibition of endoplasmic reticulum stress counteracts neuronal cell death and protein aggregation caused by N-terminal mutant huntingtin proteins. Exp Cell Res. 2008;314:950–960.
  • Reijonen S, Kukkonen JP, Hyrskyluoto A, et al. Downregulation of NF-kappaB signaling by mutant huntingtin proteins induces oxidative stress and cell death. Cell Mol Life Sci. 2010;67:1929–1941.
  • Kumar A, Kumar V, Singh K, et al. Therapeutic advances for Huntington’s disease. Brain Sci. 2020;10:E43.
  • Crews L, Masliah E. Molecular mechanisms of neurodegeneration in Alzheimer’s disease. Hum Mol Genet. 2010;19(R1):R12–R20.
  • McAvoy K, Kawamata H. Glial mitochondrial function and dysfunction in health and neurodegeneration. Mol Cell Neurosci. 2019;101:103417.
  • Angelova PR, Esteras N, Abramov AY. Mitochondria and lipid peroxidation in the mechanism of neurodegeneration: finding ways for prevention. Med Res Rev. 2020 Jul 13. DOI:10.1002/med.21712. Epub ahead of print. PMID:32656815.
  • Su TP, London ED, Jaffe JH. Steroid binding at sigma receptors suggests a link between endocrine, nervous, and immune systems. Science. 1988;240:219–221.
  • Fontanilla D, Johannessen M, Hajipour AR, et al. The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator. Science. 2009;323:934–937.
  • Brailoiu E, Chakraborty S, Brailoiu GC, et al. Choline is an intracellular messenger linking extracellular stimuli to IP3-evoked Ca2+ signals through sigma-1 receptors. Cell Rep. 2019;26(330–337.e4). DOI:10.1016/j.celrep.2018.12.051
  • Hayashi T, Su TP. Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca2+ signaling and cell survival. Cell. 2007;131:596–610.
  • Meunier J, Hayashi T. Sigma-1 receptors regulate Bcl-2 expression by reactive oxygen species-dependent transcriptional regulation of nuclear factor kappaB. J Pharmacol Exp Ther. 2010;332:388–397.
  • Hayashi T, Maurice T, Su TP. Ca2+ signaling via sigma1-receptors: novel regulatory mechanism affecting intracellular Ca2+ concentration. J Pharmacol Exp Ther. 2000;293:788–798.
  • Goguadze N, Zhuravliova E, Morin D, et al. Sigma-1 receptor agonists induce oxidative stress in mitochondria and enhance complex I activity in physiological condition, but protect against pathological oxidative stress. Neurotox Res. 2019;35:1–18.
  • Tsai SY, Chuang JY, Tsai MS, et al. Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope. Proc Natl Acad Sci USA. 2015;112:E6562–70.
  • Arun AS, Eddings CR, Wilson KL. Novel missense alleles of SIGMAR1 as tools to understand emerin-dependent gene silencing in response to cocaine. Exp Biol Med (Maywood). 2019;244:1354–1361.
  • Hayashi T, Tsai SY, Mori T, et al. Targeting ligand-operated chaperone sigma-1 receptors in the treatment of neuropsychiatric disorders. Expert Opin Ther Targets. 2011;15:557–577.
  • Maurice T, Goguadze N. Sigma-1 (σ1) receptor in memory and neurodegenerative diseases. Handb Exp Pharmacol. 2017;244:81–108.
  • Benarroch EE. Sigma-1 receptor and amyotrophic lateral sclerosis. Neurology. 2018;91:743–747.
  • Vavers E, Zvejniece L, Maurice T, et al. Allosteric modulators of sigma-1 receptor: a review. Front Pharmacol. 2019;10:223.
  • Ryskamp D, Wu L, Wu J, 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.
  • 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.
  • Delprat B, Crouzier L, Su TP, et al. At the crossing of ER stress and MAMs: a key role of sigma-1 receptor? Adv Exp Med Biol. 2020;1131:699–718.
  • Hampel H, Afshar M, Parmentier F, et al. Longitudinal 148-week update of ANAVEX®2-73 phase 2a Alzheimer’s disease extension study. J Prev Alzh Dis. 2018;5:S43.
  • Schneider LS, Thomas RG, Hendrix S, 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 Jul 8;76:1330.
  • McCallister E. Lessons from healey als on how to build platform trials quickly. BioCentury. 2019;303490.
  • Reilmann R, McGarry A, Grachev ID, 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;18:165–176.
  • Su TP. Non-canonical targets mediating the action of drugs of abuse: cocaine at the sigma-1 receptor as an example. Front Neurosci. 2019;13:761.
  • Paillusson S, Stoica R, Gomez-Suaga P, et al. There’s something wrong with my MAM; the ER-mitochondria axis and neurodegenerative diseases. Trends Neurosci. 2016;39:146–157.
  • Rodríguez-Arribas M, SMS Y-D, Pedro JMB, et al. Mitochondria-associated membranes (MAMs): overview and its role in Parkinson’s disease. Mol Neurobiol. 2017;54:6287–6303.
  • Hedskog L, Pinho CM, Filadi R, et al. Modulation of the endoplasmic. reticulum-mitochondria interface in Alzheimer’s disease and related models. Proc Natl Acad Sci USA. 2013;110:7916–7921.
  • Area-Gomez E, Del Carmen Lara Castillo M, Tambini MD, et al. Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. Embo J. 2012 Nov 5;31(21):4106–4123.
  • Liu CC, Liu CC, Kanekiyo T, et al. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9:106–118.
  • Guardia-Laguarta C, Area-Gomez E, Rüb C, et al. α-Synuclein is localized to mitochondria-associated ER membranes. J Neurosci. 2014;34:249–259.
  • Panov AV, Gutekunst CA, Leavitt BR, et al. Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nat Neurosci. 2002;5:731–736.
  • Atwal RS, Xia J, Pinchev D, et al. Huntingtin has a membrane association signal that can modulate huntingtin aggregation, nuclear entry and toxicity. Hum Mol Genet. 2007;16:2600–2615.
  • Stoica R, De Vos KJ, Paillusson S, et al. ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43. Nat Commun. 2014;5:3996.
  • Khalil B, Cabirol-Pol MJ, Miguel L, et al. Enhancing Mitofusin/Marf ameliorates neuromuscular dysfunction in Drosophila models of TDP-43 proteinopathies. Neurobiol Aging. 2017;54:71–83.
  • Mháille AN, McQuaid S, Windebank A, et al. Increased expression of endoplasmic reticulum stress-related signaling pathway molecules in multiple sclerosis lesions. J Neuropathol Exp Neurol. 2008;67:200–211.
  • Haile Y, Deng X, Ortiz-Sandoval C, et al. Rab32 connects ER stress to mitochondrial defects in multiple sclerosis. J Neuroinflammation. 2017;14:19.
  • Marrazzo A, Caraci F, Salinaro ET, et al. Neuroprotective effects of sigma-1 receptor agonists against beta-amyloid-induced toxicity. Neuroreport. 2005;16:1223–1226.
  • Behensky AA, Yasny IE, Shuster AM, et al. Afobazole activation of σ-1 receptors modulates neuronal responses to amyloid-β25-35. J Pharmacol Exp Ther. 2013;347:468–477.
  • Behensky AA, Yasny IE, Shuster AM, et al. Stimulation of sigma receptors with afobazole blocks activation of microglia and reduces toxicity caused by amyloid-β25-35. J Pharmacol Exp Ther. 2013;347:458–467.
  • Meunier J, Ieni J, Maurice T. The anti-amnesic and neuroprotective effects of donepezil against amyloid β25-35 peptide-induced toxicity in mice involve an interaction with the σ1 receptor. Br J Pharmacol. 2006;149:998–1012.
  • Villard V, Espallergues J, Keller E, et al. Antiamnesic and neuroprotective effects of the aminotetrahydrofuran derivative ANAVEX1-41 against amyloid β25-35-induced toxicity in mice. Neuropsychopharmacology. 2009;34:1552–1566.
  • Villard V, Espallergues J, Keller E, et al. Anti-amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigma 1 (σ1) ligand ANAVEX2–73, a novel aminotetrahydrofuran derivative. J Psychopharmacol. 2011;25:1101–1117.
  • Aly HF, Metwally FM, Ahmed HH. Neuroprotective effects of dehydroepiandrosterone (DHEA) in rat model of Alzheimer’s disease. Acta Biochim Pol. 2011;58:513–520.
  • Antonini V, Marrazzo A, Kleiner G, et al. Anti-amnesic and neuroprotective actions of the sigma-1 receptor agonist (-)-MR22 in rats with selective cholinergic lesion and amyloid infusion. J Alzheimers Dis. 2011;24:569–586.
  • Yang R, Chen L, Wang H, et al. Anti-amnesic effect of neurosteroid PREGS in Aβ25-35-injected mice through σ1 receptor- and α7nAChR-mediated neuroprotection. Neuropharmacology. 2012;63:1042–1050.
  • Lahmy V, Meunier J, Malmström S, et al. Blockade of Tau hyperphosphorylation and Aβ1-42 generation by the aminotetrahydrofuran derivative ANAVEX2-73, a mixed muscarinic and σ1 receptor agonist, in a nontransgenic mouse model of Alzheimer’s disease. Neuropsychopharmacology. 2013;38:1706–1723.
  • Fisher A, Bezprozvanny I, Wu L, et al. AF710B, a novel M1/σ1 agonist with therapeutic efficacy in animal models of Alzheimer’s disease. Neurodegener Dis. 2016;16:95–110.
  • Hall H, Iulita MF, Gubert P, 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;14:811–823.
  • Christ MG, Huesmann H, Nagel H, et al. Sigma-1 receptor activation induces autophagy and increases proteostasis capacity in vitro and in vivo. Cells. 2019;8:E211.
  • Francardo V, Bez F, Wieloch T, et al. Pharmacological stimulation of sigma-1 receptors has neurorestorative effects in experimental parkinsonism. Brain. 2014;137:1998–2014.
  • Francardo V, Geva M, Bez F, et al. pridopidine induces functional neurorestoration via the sigma-1 receptor in a mouse model of Parkinson’s disease. Neurotherapeutics. 2019;16:465–479.
  • Voronin MV, Kadnikov IA, Voronkov DN, et al. Chaperone Sigma1R mediates the neuroprotective action of afobazole in the 6-OHDA model of Parkinson’s disease. Sci Rep. 2019;9:17020.
  • Guo CH, Cao T, Zheng LT, et al. Development and characterization of an inducible Dicer conditional knockout mouse model of Parkinson’s disease: validation of the antiparkinsonian effects of a sigma-1 receptor agonist and dihydromyricetin. Acta Pharmacol Sin. 2020;41:499–507.
  • Al-Saif A, Al-Mohanna F, Bohlega S. A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis. Ann Neurol. 2011;70:913–919.
  • Watanabe S, Ilieva H, Tamada H, et al. Mitochondria-associated membrane collapse is a common pathomechanism in SIGMAR1- and SOD1-linked ALS. EMBO Mol Med. 2016;8:1421–1437.
  • Izumi Y, Morino H, Miyamoto R, et al. Compound heterozygote mutations in the SIGMAR1 gene in an oldest-old patient with amyotrophic lateral sclerosis. Geriatr Gerontol Int. 2018;18:1519–1520.
  • Couly S, Khalil B, Viguier V, et al. Sigma-1 receptor is a key genetic modulator in amyotrophic lateral sclerosis. Hum Mol Genet. 2019;ddz267. DOI:10.1093/hmg/ddz267
  • Mavlyutov TA, Epstein ML, Verbny YI, et al. Lack of sigma-1 receptor exacerbates ALS progression in mice. Neuroscience. 2013;240:129–134.
  • Mancuso R, Oliván S, Rando A, et al. Sigma-1R agonist improves motor function and motoneuron survival in ALS mice. Neurotherapeutics. 2012;9:814–826.
  • Ono Y, Tanaka H, Takata M, et al. SA4503, a sigma-1 receptor agonist, suppresses motor neuron damage in in vitro and in vivo amyotrophic lateral sclerosis models. Neurosci Lett. 2014;559:174–178.
  • Peviani M, Salvaneschi E, Bontempi L, 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;62:218–232.
  • Hyrskyluoto A, Pulli I, Törnqvist K, et al. 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:e646.
  • Miki Y, Tanji K, Mori F, et al. Sigma-1 receptor is involved in degradation of intranuclear inclusions in a cellular model of Huntington’s disease. Neurobiol Dis. 2015;74:25–31.
  • Pettersson F, Pontén H, Waters N, et al. Synthesis and evaluation of a set of 4-phenylpiperidines and 4-phenylpiperazines as D2 receptor ligands and the discovery of the dopaminergic stabilizer 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine (huntexil, pridopidine, ACR16). J Med Chem. 2010;53:2510–2520.
  • Sahlholm K, Århem P, Fuxe K, et al. The dopamine stabilizers ACR16 and (-)-OSU6162 display nanomolar affinities at the σ-1 receptor. Mol Psychiatry. 2013;18:12–14.
  • Johnston TH, Geva M, Steiner L, et al. Pridopidine, a clinic-ready compound, reduces 3,4-dihydroxyphenylalanine-induced dyskinesia in Parkinsonian macaques. Mov Disord. 2019;34:708–716.
  • Sahlholm K, Sijbesma JW, Maas B, et al. Pridopidine selectively occupies sigma-1 rather than dopamine D2 receptors at behaviorally active doses. Psychopharmacology (Berl). 2015;232:3443–3453.
  • Ionescu A, Gradus T, Altman T, et al. Targeting the sigma-1 receptor via pridopidine ameliorates central features of ALS pathology in a SOD1G93A model. Cell Death Dis. 2019;10:210.
  • Squitieri F, Di Pardo A, Favellato M, et al. Pridopidine, a dopamine stabilizer, improves motor performance and shows neuroprotective effects in Huntington disease R6/2 mouse model. J Cell Mol Med. 2015;19:2540–2548.
  • Geva M, Kusko R, Soares H, et al. Pridopidine activates neuroprotective pathways impaired in Huntington disease. Hum Mol Genet. 2016;25:3975–3987.
  • Garcia-Miralles M, Geva M, Tan JY, et al. Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice. JCI Insight. 2017;2:95665.
  • Eddings CR, Arbez N, Akimov S, et al. Pridopidine protects neurons from mutant-huntingtin toxicity via the sigma-1 receptor. Neurobiol Dis. 2019;129:118–129.
  • Smith-Dijak AI, Nassrallah WB, Zhang LYJ, et al. Impairment and restoration of homeostatic plasticity in cultured cortical neurons from a mouse model of Huntington disease. Front Cell Neurosci. 2019;13:209.
  • Calabrese EJ, Baldwin LA. Hormesis: a generalizable and unifying hypothesis. Crit Rev Toxicol. 2001;31:353–424.
  • Calabrese EJ, Baldwin LA. Defining hormesis. Hum Exp Toxicol. 2002;21:91–97.
  • Calabrese EJ. Neuroscience and hormesis: overview and general findings. Crit Rev Toxicol. 2008;38:249–252.
  • Calabrese EJ. Hormesis and medicine. Br J Clin Pharmacol. 2008;66:594–617.
  • Lucas G, Rymar VV, Sadikot AF, et al. Further evidence for an antidepressant potential of the selective sigma1 agonist SA 4503: electrophysiological, morphological and behavioural studies. Int J Neuropsychopharmacol. 2008;11:485–495.
  • Roman FJ, Pascaud X, Duffy O, et al. Modulation by neuropeptide Y and peptide YY of NMDA effects in hippocampal slices: role of σ1 receptors. In: Kameyama T, Nabeshima T, Domino EF, editors. NMDA related agents: biochemistry, pharmacology and behavior. Ann Arbor: NPP Books; 1991. p. 211–218.
  • Monnet FP, Blier P, Debonnel G, et al. Modulation by sigma ligands of N-methyl-D-aspartate-induced [3H]noradrenaline release in the rat hippocampus: G-protein dependency. Naunyn Schmiedebergs Arch Pharmacol. 1992;346:32–39.
  • Monnet FP, Debonnel G, Junien JL, et al. N-methyl-D-aspartate-induced neuronal activation is selectively modulated by σ1 receptors. Eur J Pharmacol. 1990;179:441–445.
  • Monnet FP, Debonnel G, De Montigny C. In vivo electrophysiological evidence for a selective modulation of N-methyl-D-aspartate-induced neuronal activation in rat CA3 dorsal hippocampus by σ1 ligands. J Pharmacol Exp Ther. 1992;261:123–130.
  • Bergeron R, de Montigny C, Debonnel G. Biphasic effects of sigma ligands on the neuronal response to N-methyl-D-aspartate. Naunyn Schmiedebergs Arch Pharmacol. 1995;351:252–260.
  • Monnet FP, de Costa BR, Bowen WD. Differentiation of sigma ligand-activated receptor subtypes that modulate NMDA-evoked [3H]-noradrenaline release in rat hippocampal slices. Br J Pharmacol. 1996;119:65–72.
  • Bermack JE, Debonnel G. The role of sigma receptors in depression. J Pharmacol Sci. 2005;97:317–336.
  • Bergeron R, Debonnel G. Effects of low and high doses of selective sigma ligands: further evidence suggesting the existence of different subtypes of sigma receptors. Psychopharmacology (Berl). 1997;129:215–224.
  • McLarnon J, Sawyer D, Church J. The actions of L-687,384, a sigma receptor ligand, on NMDA-induced currents in cultured rat hippocampal pyramidal neurons. Neurosci Lett. 1994;174:181–184.
  • Peeters M, Romieu P, Maurice T, et al. Involvement of the sigma1 receptor in the modulation of dopaminergic transmission by amantadine. Eur J Neurosci. 2004;19:2212–2220.
  • Maurice T, Hiramatsu M, Itoh J, et al. Low dose of 1,3-di(2-tolyl)guanidine (DTG) attenuates MK-801-induced spatial working memory impairment in mice. Psychopharmacology (Berl). 1994;114:520–522.
  • Maurice T, Hiramatsu M, Itoh J, et al. Behavioral evidence for a modulating role of sigma ligands in memory processes. I. Attenuation of dizocilpine (MK-801)-induced amnesia. Brain Res. 1994;647:44–56.
  • Maurice T, Su TP, Parish DW, et al. PRE-084, a sigma selective PCP derivative, attenuates MK-801-induced impairment of learning in mice. Pharmacol Biochem Behav. 1994;49:859–869.
  • Maurice T, Privat A. SA4503, a novel cognitive enhancer with sigma1 receptor agonist properties, facilitates NMDA receptor-dependent learning in mice. Eur J Pharmacol. 1997;328:9–18.
  • Senda T, Matsuno K, Okamoto K, et al. Ameliorating effect of SA4503, a novel sigma 1 receptor agonist, on memory impairments induced by cholinergic dysfunction in rats. Eur J Pharmacol. 1996;315:1–10.
  • Espallergues J, Lapalud P, Christopoulos A, et al. Involvement of the sigma1 (σ1) receptor in the anti-amnesic, but not antidepressant-like, effects of the aminotetrahydrofuran derivative ANAVEX1-41. Br J Pharmacol. 2007;152:267–279.
  • Maurice T, Roman FJ, Su TP, et al. Beneficial effects of sigma agonists on the age-related learning impairment in the senescence-accelerated mouse (SAM). Brain Res. 1996;733:219–230.
  • Senda T, Matsuno K, Kobayashi T, et al. Ameliorative effect of SA4503, a novel cognitive enhancer, on the basal forebrain lesion-induced impairment of the spatial learning performance in rats. Pharmacol Biochem Behav. 1998;59:129–134.
  • Maurice T, Su TP, Privat A. Sigma1 (σ1) receptor agonists and neurosteroids attenuate β25-35-amyloid peptide-induced amnesia in mice through a common mechanism. Neuroscience. 1998;83:413–428.
  • Zvejniece L, Vavers E, Svalbe B, et al. The cognition-enhancing activity of E1R, a novel positive allosteric modulator of sigma-1 receptors. Br J Pharmacol. 2014;171:761–771.
  • Maurice T, Volle JN, Strehaiano M, et al. Neuroprotection in non-transgenic and transgenic mouse models of Alzheimer’s disease by positive modulation of σ1 receptors. Pharmacol Res. 2019;144:315–330.
  • Martin P, de Witte PAM, Maurice T, et al. Fenfluramine acts as a positive modulator of sigma-1 receptors. Epilep Behav. 2020;105:106989.in press.
  • Pande AC, Genève J, Scherrer B, et al. A placebo-controlled trial of igmesine in the treatment of major depression. Eur Neuropsychopharmacol. 1999;9:S138.
  • Wilke RA, Mehta RP, Lupardus PJ, et al. Sigma receptor photolabeling and sigma receptor-mediated modulation of potassium channels in tumor cells. J Biol Chem. 1999;274:18387–18392.
  • Hayashi T, Su TP. Regulating ankyrin dynamics: roles of sigma-1 receptors. Proc Natl Acad Sci USA. 2001;98:491–496.
  • Johannessen M, Ramachandran S, Riemer L, et al. Voltage-gated sodium channel modulation by sigma-receptors in cardiac myocytes and heterologous systems. Am J Physiol Cell Physiol. 2009;296:C1049–57.
  • Carnally SM, Johannessen M, Henderson RM, et al. Demonstration of a direct interaction between sigma-1 receptors and acid-sensing ion channels. Biophys J. 2010;98:1182–1191.
  • Kim FJ, Kovalyshyn I, Burgman M, et al. Sigma 1 receptor modulation of G-protein-coupled receptor signaling: potentiation of opioid transduction independent from receptor binding. Mol Pharmacol. 2010;77:695–703.
  • Chu UB, Ruoho AE. Biochemical pharmacology of the Sigma-1 receptor. Mol Pharmacol. 2016;89:142–153.
  • Mishra AK, Mavlyutov T, Singh DR, et al. The sigma-1 receptors are present in monomeric and oligomeric forms in living cells in the presence and absence of ligands. Biochem J. 2015;466:263–271.
  • Su TP, Su TC, Nakamura Y, et al. The Sigma-1 receptor as a pluripotent modulator in living systems. Trends Pharmacol Sci. 2016;37:262–278.
  • Soriani O, Kourrich S. The Sigma-1 receptor: when adaptive regulation of cell electrical activity contributes to stimulant addiction and cancer. Front Neurosci. 2019;13:1186.
  • de Lau LM, Breteler MM. Epidemiology of Parkinson’s disease. Lancet Neurol. 2006;5:525–535.
  • Hayashi T, Su TP. Sigma-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;306:718–725.
  • Hayashi T, Su TP. Intracellular dynamics of sigma-1 receptors (σ1 binding sites) in NG108-15 cells. J Pharmacol Exp Ther. 2003;306:726–733.
  • Meunier J, Demeilliers B, Celerier A, et al. Compensatory effect by sigma1 (σ1) receptor stimulation during alcohol withdrawal in mice performing an object recognition task. Behav Brain Res. 2006a;166:166–176.
  • Kourrich S, Hayashi T, Chuang JY, et al. Dynamic interaction between sigma-1 receptor and Kv1.2 shapes neuronal and behavioral responses to cocaine. Cell. 2013;152:236–247.
  • Balasuriya D, Stewart AP, Edwardson JM. The σ-1 receptor interacts directly with GluN1 but not GluN2A in the GluN1/GluN2A NMDA receptor. J Neurosci. 2013;33:18219–18224.
  • Mavlyutov TA, Duellman T, Kim HT, et al. Sigma-1 receptor expression in the dorsal root ganglion: reexamination using a highly specific antibody. Neuroscience. 2016;331:148–157.
  • Mavlyutov TA, Epstein M, Guo LW. Subcellular localization of the sigma-1 receptor in retinal neurons - an electron microscopy study. Sci Rep. 2015;5:10689.
  • Ovalle S, Andreu F, Pérez MP, et al. Effect of the novel sigma1 receptor ligand and putative atypical antipsychotic E-5842 on BDNF mRNA expression in the rat brain. Neuroreport. 2002;13:2345–2348.
  • 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;440:19–22.
  • Fujimoto M, Hayashi T, Urfer R, et al. Sigma-1 receptor chaperones regulate the secretion of brain-derived neurotrophic factor. Synapse. 2012;66:630–639.
  • Dalwadi DA, Kim S, Schetz JA. Activation of the sigma-1 receptor by haloperidol metabolites facilitates brain-derived neurotrophic factor secretion from human astroglia. Neurochem Int. 2017;105:21–31.
  • Yagasaki Y, Numakawa T, Kumamaru E, et al. Chronic antidepressants potentiate via sigma-1 receptors the brain-derived neurotrophic factor-induced signaling for glutamate release. J Biol Chem. 2006;281:12941–12949.
  • Ring RM, Regan CM. Captodiamine, a putative antidepressant, enhances hypothalamic BDNF expression in vivo by synergistic 5-HT2c receptor antagonism and sigma-1 receptor agonism. J Psychopharmacol. 2013;27:930–939.
  • Mamounas LA, Blue ME, Siuciak JA, et al. Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain. J Neurosci. 1995;15:7929–7939.
  • Mamounas LA, Altar CA, Blue ME, et al. BDNF promotes the regenerative sprouting, but not survival, of injured serotonergic axons in the adult rat brain. J Neurosci. 2000;20:771–782.
  • Boyd JG, Gordon T. A dose-dependent facilitation and inhibition of peripheral nerve regeneration by brain-derived neurotrophic factor. Eur J Neurosci. 2002;15:613–626.
  • Xu J, Zeng C, Chu W, et al. Identification of the PGRMC1 protein complex as the putative sigma-2 receptor binding site. Nat Commun. 2011;2:380.
  • Alon A, Schmidt HR, Wood MD, et al. Identification of the gene that codes for the σ2 receptor. Proc Natl Acad Sci USA. 2017;114:7160–7165.
  • Longhitano L, Castracani CC, Tibullo D, et al. Sigma-1 and Sigma-2 receptor ligands induce apoptosis and autophagy but have opposite effect on cell proliferation in uveal melanoma. Oncotarget. 2017;8:91099–91111.
  • Wei Z, Mousseau DD, Dai Y, et al. Haloperidol induces apoptosis via the σ2 receptor system and Bcl-XS. Pharmacogenomics J. 2006;6:279–288.
  • Katnik C, Garcia A, Behensky AA, et al. Treatment with afobazole at delayed time points following ischemic stroke improves long-term functional and histological outcomes. Neurobiol Dis. 2014;62:354–364.
  • Katnik C, Garcia A, Behensky AA, et al. Activation of σ1 and σ2 receptors by afobazole increases glial cell survival and prevents glial cell activation and nitrosative stress after ischemic stroke. J Neurochem. 2016;139:497–509.
  • Tesei A, Cortesi M, Zamagni A, et al. sigma receptors as endoplasmic reticulum stress “gatekeepers” and their modulators as emerging new weapons in the fight against cancer. Front Pharmacol. 2018;9:711.
  • Grundman M, Morgan R, Lickliter JD, 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;5:20–26.
  • Yi B, Sahn JJ, Ardestani PM, 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;140:561–575.
  • Izzo NJ, Xu J, Zeng C, et al. Alzheimer’s therapeutics targeting amyloid beta 1-42 oligomers II: sigma-2/PGRMC1 receptors mediate Aβ42 oligomer binding and synaptotoxicity. PLoS One. 2014;9:e111899.
  • Tesei A, Cortesi M, Pignatta S, et al. Anti-tumor efficacy assessment of the sigma receptor pan modulator RC-106. A promising therapeutic tool for pancreatic cancer. Front Pharmacol. 2019;10:490.
  • Seredenin SB, Antipova TA, Voronin MV, et al. Interaction of afobazole with sigma1-receptors. Bull Exp Biol Med. 2009;148:42–44.
  • Narita N, Hashimoto K, Tomitaka S, et al. Interactions of selective serotonin reuptake inhibitors with subtypes of sigma receptors in rat brain. Eur J Pharmacol. 1996;307:117–119.
  • Takebayashi M, Hayashi T, Su TP. Nerve growth factor-induced neurite sprouting in PC12 cells involves sigma-1 receptors: implications for antidepressants. J Pharmacol Exp Ther. 2002;303:1227–1237.
  • Hashimoto K, Fujita Y, Iyo M. Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of fluvoxamine: role of sigma-1 receptors. Neuropsychopharmacology. 2007;32:514–521.
  • Werling LL, Lauterbach EC, Calef U. Dextromethorphan as a potential neuroprotective agent with unique mechanisms of action. Neurologist. 2007;13:272–293.
  • Nguyen L, Robson MJ, Healy JR, et al. Involvement of sigma-1 receptors in the antidepressant-like effects of dextromethorphan. PLoS One. 2014;9:e89985.
  • Maurice T, Meunier J, Feng B, et al. Interaction with sigma1 protein, but not N-methyl-D-aspartate receptor, is involved in the pharmacological activity of donepezil. J Pharmacol Exp Ther. 2006;317:606–614.
  • Hampel H, Williams C, Etcheto A, 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:e12013.
  • Schmidt HR, Betz RM, Dror RO, et al. Structural basis for σ1 receptor ligand recognition. Nat Struct Mol Biol. 2018;25:981–987.
  • Mavylutov T, Chen X, Guo L, et al. APEX2- tagging of Sigma 1-receptor indicates subcellular protein topology with cytosolic N-terminus and ER luminal C-terminus. Protein Cell. 2018;9:733–737.
  • Gordon DE, Jang GM, Bouhaddou M, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020;583:459–468.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.