Agonists at the s1 receptor, by exerting beneficial effects on memory processes and depression and showing marked neuroprotective effects, may offer new therapeutic potential in treating Alzheimer's disease.
Improving Alzheimer's Disease-Related Cognitive Deficits with s1 Receptor Agonists
by Tangui Maurice
Treating dementia of the Alzheimer's type is a terrible challenge that will require an innovative pharmacological strategy simultaneously addressing symptoms and causes of the complex neurodegenerative process involved in Alzheimer's disease. The present review will outline the most recent data, albeit restricted to preliminary preclinical studies, suggesting that the s1 receptor agonist may present some efficacy. The s1 receptor is a unique intraneuronal protein that modulates intracellular Ca2+ mobilization and extracellular Ca2+ influx, leading to a wide spectrum of neuromodulatory activity. At the behavioral level, s1-receptor agonists are antiamnesic and anti-depressant drugs. The s1 receptor is also one of the receptors at which neurosteroids act to exert their rapid nongenomic effects in the brain. In particular, dehydroepiandrosterone (DHEA) is an endogenous s1 agonist and progesterone, a potent antagonist of the s1 receptor. The b-amyloid protein-related toxicity induces important disturbances of neurosteroid syntheses and releases mechanisms, particularly by affecting the corticotropin-releasing hormone systems. In turn, s1-receptor agonists showed an enhanced efficacy in animal models of Alzheimer's disease-related learning impairments or depressive responses. In addition, selective s1 agonists, as well as DHEA, showed marked neuroprotective activity in vitro against oxidative stress-related damages. Acting chronically through the s1 receptor may indeed offer a new way to alleviate the cognitive disturbances observed in Alzheimer's disease and promote long-term improvements. © 2002 Prous Science. All rights reserved.
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