Neuroprotective and anti-amnesic potentials of sigma (σ) receptor ligands

Abstract

Although the physical nature of sigma (σ) receptors have not yet been fully defined, several classes of selective ligands have been characterised, demonstrating a plethora of physiological actions. In the present review, the authors have set out to highlight two important aspects of the biological activities of σ ligands, their neuroprotective and anti-amnesic effects. The σ ligands present a therapeutic potential as neuroprotective agents in brain ischemia. The neuroprotective activity of many non-selective σ ligands is primarily a result of their affinity for the NMDA receptor complex. However, selective σ ligands are also neuroprotective, possibly by inhibition of the ischemic-induced presynaptic release of excitotoxic amino acids. The σ1 ligands prevent the experimental amnesia induced by muscarinic cholinergic antagonists at either the learning, consolidation or retention phase of the mnesic process. This effect involves a potentiation of acetylcholine release induced by σ1 ligands selectively in the hippocampal formation and cortex. The σ1 receptor ligands also attenuate the learning impairment induced by dizocilpine, a non-competitive antagonist of the NMDA receptor, and may relate to the potentiating effect of σ1 ligands on several NMDA receptor-mediated responses previously described in vitro and in vivo in the hippocampus. This effects is shared by NPY- and CGRP-related peptides and by neuroactive steroids, confirming the in vitro evidences of functional interactions between the σ1 receptors and these different systems. Additional amnesia models also seem to be alleviated by σ1 ligands, such as phencyclidine-induced cognitive dysfunctions, and amnesia induced by the calcium channel blocker nimodipine, or by exposure to carbon monoxide. Furthermore, a preliminary study in an animal model of age-related memory deficits, the senescence-accelerated mouse, strengthened the therapeutic potentials of selective σ1 receptor ligands in aging-related pathologies.