Anavex Life Sciences Corp. ("Anavex" or the "Company") (OTCQB: AVXL) has announced that the current issue of the peer-reviewed scientific journal PLOS ONE explains that sigma-1 receptor (Sig-1R) activity is involved in cellular survival by regulating and stabilizing a key cell stress sensor. These findings may explain the therapeutic efficacy of Sig-1R agonists like ANAVEX 2-73 in Alzheimer's disease and other neurodegenerative disorders.
According to the published report, when cells are under endoplasmic reticulum (ER) stress, the key ER stress sensor 'IRE1' induces the upregulation of critical signaling for survival and thus prevents IRE1 from triggering apoptosis (cell death). These results indicate a cellular protective action of Sig-1Rs, which could make a difference preventing cell degeneration as observed in Alzheimer's disease.
The study authors conclude that the Sig-1R molecular chaperone enhances its association with IRE1 to correct or stabilize the conformation of IRE1 when cells are facing ER stress. Without Sig-1Rs, the authors find IRE1 is vulnerable to proteasomal degradation eventually triggering apoptosis.
"When ER stress is caused by accumulation of misfolded proteins in the cell, the unfolded protein response (UPR) is triggered as a cellular stress response. The aim of these responses is to remove the accumulated protein load while preventing any further addition to the stress, so that normal function of the ER can be restored as soon as possible," said Tangui Maurice, PhD, CNRS Research Director, Head of Team 2 'Endogenous Neuroprotection in Neurodegenerative Diseases', at the University of Montpellier and INSERM. "However, in conditions of prolonged stress, when the level of unfolded proteins exceeds a threshold, the cell might commit suicide by activating the cell death pathways and the goal of the UPR changes from being one that promotes cellular survival to one that commits the cell to a pathway of apoptosis. In contrast, sustained activation of the IRE1 pathway constitutively promotes survival against ER stress."
"The sustenance of the IRE1 stability through Sig-1R might promote critically needed cellular survival and this represents an important advance in our understanding of the potential mechanisms by which our mixed Sig-1R and muscarinic drug candidate ANAVEX 2-73 might exert its neuroprotective effects," said Christopher U. Missling, PhD, President and Chief Executive Officer of Anavex. "Recently, we have seen that ANAVEX 2-73 shows anti-amnesic and neuroprotective potential against amyloid-beta toxicity, and reduces mitochondrial oxidative stress, cellular loss and memory deficits in models of Alzheimer's disease. In this regard, it is interesting to note that these reported preclinical studies describing the potential therapeutic efficacies of ANAVEX 2-73 in ameliorating amyloid-beta-induced neurodegeneration might be putatively explained by this new report through its Sig-1R activity."
The report, entitled "Sigma-1 Receptor Chaperone at the ER-Mitochondrion Interface Mediates the Mitochondrion-ER-Nucleus Signaling for Cellular Survival," was performed by Dr Tsung-Ping Su and his colleagues at the laboratory of the Cellular Pathobiology Section, Intramural Research Program/NIDA/NIH/DHHS, Baltimore, Maryland.