Sigma-1 (σ1) Receptor in Memory and Neurodegenerative Diseases

Abstract

The sigma-1 (σ) receptor has been associated with regulation of intracellular Ca homeostasis, several cellular signaling pathways, and inter-organelle communication, in part through its chaperone activity. In vivo, agonists of the σ receptor enhance brain plasticity, with particularly well-described impact on learning and memory. Under pathological conditions, σ receptor agonists can induce cytoprotective responses. These protective responses comprise various complementary pathways that appear to be differentially engaged according to pathological mechanism. Recent studies have highlighted the efficacy of drugs that act through the σ receptor to mitigate symptoms associated with neurodegenerative disorders with distinct mechanisms of pathogenesis. Here, we will review genetic and pharmacological evidence of σ receptor engagement in learning and memory disorders, cognitive impairment, and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Huntington's disease.

Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice

“…Activation of S1R has been shown to be neuroprotective in a number of experimental paradigms (50). In relation to HD, the S1R agonist, PRE084, was shown to enhance cellular antioxidant defences and to protect against mHTT-induced toxicity in a rat neuronal cell line (18).…”

Pridopidine stabilizes mushroom spines in mouse models of Alzheimer's disease by acting on the sigma-1 receptor

“…S1R agonists are procognitive, synaptogenetic and neuroprotective in conditions of neuronal stress (Antonini et al, 2009;Bolshakova et al, 2016;Hindmarch and Hashimoto, 2010;Ruscher et al, 2011) and as a result they are beneficial in experimental models of Huntington's disease (HD) (Bol'shakova et al, 2017;Ryskamp et al, 2017;Squitieri et al, 2015) (Garcia-Miralles et al, 2017Geva et al, 2016;Kusko et al, 2018), Parkinson's disease (Francardo et al, 2014) and AD (Fisher et al, 2016;Hall et al, 2017;Maurice and Goguadze, 2017;Meunier et al, 2006). For example, we discovered that the mixed muscarinic/S1R agonist AF710B prevents the loss of mushroom spines in hippocampal cultures prepared from APP-KI or PS1-KI mice (Fisher et al, 2016).…”

“…Also, the acetylcholine esterase inhibitor donepezil, which is approved for use in the treatment of AD, is a high affinity S1R agonist and its anti-amnestic and neuroprotective properties may be partially mediated by S1R (Meunier et al, 2006). In APP Swe AD mice knockout of S1R increases oxidative stress in the hippocampus and promotes memory deficits (Maurice and Goguadze, 2017;Maurice et al, 2018). These and other examples (Mancuso et al, 2012;Maurice and Lockhart, 1997;Mavlyutov et al, 2013;Mavlyutov et al, 2011;Nakazawa et al, 1998;Ono et al, 2014;Ryskamp et al, 2017;Smith et al, 2008) show that S1R agonists are broadly neuroprotective and loss of S1R worsens neurodegenerative phenotypes.…”

“…Interestingly, common genetic variants of S1R may modify risk of AD in carriers of the APOE ε4 allele (Fehér et al, 2012;Huang et al, 2011;Maruszak et al, 2007;Uchida et al, 2005). S1R agonists have antiamnestic properties, rescuing learning and memory impairments from scopolamine or amyloid-β toxicity (Maurice and Goguadze, 2017). S1R agonists also modulate several neuroprotective pathways and have demonstrated preclinical efficacy in animal models of AD.…”

“…Several other S1R agonists including PRE-084, (-)-MR22, ANAVEX1-41, ANAVEX2-73, DHEA, and pregnenolone sulfate treat the hallmarks of AD in vivo following injection of Aβ 25-35 into the CNS of rodents by reducing Aβ 1-42 , GSK-3β activity, hyperphosphorylated Tau, neuroinflammation, oxidative stress, endoplasmic reticulum (ER) stress, apoptosis of hippocampal neurons and memory impairments (Maurice and Goguadze, 2017;Meunier et al, 2006). Also, the acetylcholine esterase inhibitor donepezil, which is approved for use in the treatment of AD, is a high affinity S1R agonist and its anti-amnestic and neuroprotective properties may be partially mediated by S1R (Meunier et al, 2006).…”