Improving Alzheimer's Disease-Related Cognitive Deficits with sigma1 Receptor Agonists

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 sigma(1) receptor agonist may present some efficacy. The sigma(1) receptor is a unique intraneuronal protein that modulates intracellular Ca(2+) mobilization and extracellular Ca(2+) influx, leading to a wide spectrum of neuromodulatory activity. At the behavioral level, sigma(1)-receptor agonists are antiamnesic and anti-depressant drugs. The sigma(1) 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 sigma(1) agonist and progesterone, a potent antagonist of the sigma(1) receptor. The beta-amyloid protein-related toxicity induces important disturbances of neurosteroid syntheses and releases mechanisms, particularly by affecting the corticotropin-releasing hormone systems. In turn, sigma(1)-receptor agonists showed an enhanced efficacy in animal models of Alzheimer's disease-related learning impairments or depressive responses. In addition, selective sigma(1) agonists, as well as DHEA, showed marked neuroprotective activity in vitro against oxidative stress-related damages. Acting chronically through the sigma(1) receptor may indeed offer a new way to alleviate the cognitive disturbances observed in Alzheimer's disease and promote long-term improvements. (c) 2002 Prous Science. All rights reserved.