Neuroprotective effects of sigma-1 receptor agonists against beta-amyloid-induced toxicity

Abstract

Prolonged exposure of cultured cortical neurons to the residue 25-35 fragment of beta-amyloid protein, in the presence of dizocilpine, an antagonist of the N-methyl-D-aspartate receptor, and of 6,7-dinitroquinoxaline-2,3-dione, an antagonist of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors, resulted in the expression of the proapoptotic protein Bax and neuronal death. Beta-amyloid protein(25-35)-induced neuronal death was substantially attenuated by the sigma1 receptor agonist 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate. The neuroprotective action of 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate was mimicked by the sigma1 ligand methyl (1S,2R)-2-[1-adamantyl(methyl)amino]methyl-1-phenylcyclopropanecarboxylate and was antagonized by the sigma1 receptor antagonist N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine monohydrochloride. These results suggest that sigma1 receptor agonists might function as neuroprotectant agents in Alzheimer's disease.

The cholinergic system, sigma-1 receptors and cognition

“…Sigma-1 receptor agonists may have potential for treating AD since the compounds are not only capable of alleviating cognitive deficits in animal models of cognitive impairment (see above) but they can also provide neuroprotection against amyloid toxicity (see [83] for a review). Evidence for such neuroprotective activity has been provided both by in vitro experiments in cultured cortical neurons [71] and by in vivo studies in rodents [105,157]. Recently, it was found that sigma-1 receptor agonists can powerfully suppress microglial activation [29].…”

“…1). The sigma-1 receptor is implicated in cellular differentiation [37,40], neuroplasticity [145,149], neuroprotection [71,89], and cognitive functioning of the brain [85].…”

Differential Effect on Two Immobility Responses by Chronic Administration of 1,3-di-o-Tolyl-Guanidine (Sigma Receptor Agonist) in Rats with Neonatal Ventral Hippocampal Lesion

“…Occupancy of sigma-1 receptors by agonists causes translocation of the receptor protein from the endoplasmatic reticulum to the cell membrane where the receptor can regulate ion channels and neurotransmitter release [38] [41]. The sigma-1 receptor is implicated in cellular differentiation [42] [43], neuroplasticity [44] [45], neuroprotection [46] [47], and cognitive functioning of the brain [48]. Such neuroprotection and neurite outgrowth are thought to contribute to the improvement of various neuropsychiatric diseases like the schizophrenia.…”

Antiamnesic and Neuroprotective Effects of the Aminotetrahydrofuran Derivative ANAVEX1-41 Against Amyloid β25–35-Induced Toxicity in Mice

“…Modifying s 1 protein activation using selective activators/agonists therefore mediates a unique pharmacological action on Ca 2 + homeostasis and signal transduction pathways, which has proven to allow an effective neuroprotection against several kinds of insults, including excitotoxicity, oxidative stress, and amyloid toxicity (for reviews, see Maurice et al, 2006;Monnet and Maurice, 2006). Indeed, preliminary experiments showed that, in vitro, the selective s 1 activators PRE-084 and MR-22 attenuate the Ab 25-35 -induced expression of the proapoptotic protein Bax and neuronal death in rat cortical cultures (Marrazzo et al, 2005). We reported that, in vivo, PRE-084 prevents the Ab 25-35 -induced oxidative stress and learning impairments in mice (Meunier et al, 2006).…”