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

1. Although the physical nature of sigma (sigma) 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 sigma ligands, their neuroprotective and anti-amnesic effects. 2. The sigma ligands present a therapeutic potential as neuroprotective agents in brain ischemia. The neuroprotective activity of many non-selective sigma ligands is primarily a result of their affinity for the NMDA receptor complex. However, selective sigma ligands are also neuroprotective, possibly by inhibition of the ischemic-induced presynaptic release of excitotoxic amino acids. 3. The sigma 1 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 potentation of acetylcholine release induced by sigma 1 ligands selectively in the hippocampal formation and cortex. 4. The sigma 1 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 sigma 1 ligands on several NMDA receptor-mediated responses previously described in vitro and in vivo in the hippocampus. This effect is shared by NPY- and CGRP-related peptides and by neuroactive steroids, confirming the in vitro evidences of functional interactions between the sigma 1 receptors and these different systems. 5. Additional amnesia models also seem to be alleviated by sigma 1 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 sigma 1 receptor ligands in aging-related pathologies.