Pharmaceutical interest towards S1R has re-emerged given the recent advances in S1R crystal structure [6], our improved understanding of its ligand recognition/association [91,92], and biological functions. As discussed above, S1R activity in calcium homeostasis, lipid metabolism, protein folding, autophagy, ER-stress response, intracellular trafficking, gene transcription and translation, makes it a powerful target when trying to rescue or enhance any of these mechanisms that might be dysregulated in a disease. In fact, S1R is now, more than ever, considered a very potent modulator of neuroprotection and a lot of efforts are put together to take advantage of these functions to prevent, stabilize, or even modify neurodegeneration. Thus, we must mention that S1R is a therapeutic target for diseases, including AD [93], PD [94], ALS [95,96], and cancer [97]. In fact, there are ongoing phase 2/3 clinical trials for the treatment of Alzheimer’s disease[/i][url][/url][tag]insert-text-here[/tag] (NCT03790709, NCT04314934) and phase 2 trials for Parkinson’s disease dementia (NCT04575259). These trials are testing ANAVEX2-73 (also known as Blacarmesine), another compound designed as an S1R agonist (and a muscarinic modulator of M1 receptor and a M2/M3 receptors antagonist) [98]. This drug is involved in the modulation of glutamate release, suppression of neuroinflammation, and restoration of cellular functions essential for maintaining neuronal homeostasis processes such as protein folding, calcium regulation, oxidative stress, ER stress, and autophagy [18,19,47,99]. ANAVEX2-73 has shown not only neuroprotective effects but also anticonvulsant, antiamnesic, and antidepressant properties in various animal models [98,99]. Furthermore, pridopidine (also known as ACR16 or Huntexil®) is currently being investigated in a phase 2 clinical trial for the treatment of ALS (NCT04615923). Initially developed for the treatment of Huntington’s disease (HD) associated motor symptoms (reviewed in [18,100]), pridopidine has been shown to protect cells from apoptosis and to improve motor function in an HD mouse model (R6/2). It was shown to: (i) rescue mitochondrial functions and to preserve MAM integrity in human neural stem cells and an HD mouse model (YAC128) [101], (ii) reduce ER stress by modulating all branches of the UPR response in a mHtt (mutant huntingtin) cell line [102], and (iii) protect neurons from mHTT toxicity to decrease cell death [103]. Pridopidine was also shown to decrease neuron death, to conserve neuro-muscular junctions (NMJ), and to restore and enhance axonal transport in primary myocytes and motoneurons cell culture derived from wild-type and SOD1-G93A mice (ALS mouse model) [96]. As of now, targeting S1R activity in neurodegenerative disorders shows great potential. However, combining S1R agonists with other treatments needs to be considered for further analysis of beneficial outcomes. Finally, given that neurosteroids can bind to S1R and modulate its activity, more studies are required to fully understand the effect of aging and biological sex on S1R activity. These studies could help to better estimate S1R therapeutic potency when evaluating its functions in age- and sex-related neurodegenerative disorders.
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