Neuroprotection in non-transgenic and transgenic mouse models of Alzheimer's disease by positive modulation of sigma(1) receptors

摘要

The sigma-1 (sigma(1)) receptor is an endoplasmic reticulum (ER) chaperone protein, enriched in mitochondria-associated membranes. Its activation triggers physiological responses to ER stress and modulate Ca2+ mobilization in mitochondria. Small sigma(1) agonist molecules activate the protein and act behaviorally as antidepressant, anti-amnesic and neuroprotective agents. Recently, several chemically unrelated molecules were shown to be sigma(1) receptor positive modulators (PMs), with some of them a clear demonstration of their allostericity. We here examined whether a sigma(1) PM also shows neuroprotective potentials in pharmacological and genetic models of Alzheimer's disease (AD). For this aim, we describe ( +/- )-2-(3-chloropheny1)-3,3,5,5-tetramethyl-2-oxo-[1,4,2]-oxazaphosphinane (OZP002) as a novel sigma(1) PM. OZP002 does not bind sigma(1) sites but induces sigma(1) effects in vivo and boosts ch agonist activity. OZP002 was antidepressant in the forced swim test and its effect was blocked by the sigma(1) antagonist NE-100 or in sigma(1) receptor knockout mice. It potentiated the antidepressant effect of the sigma(1) agonist igmesine. In mice tested for Y-maze alternation or passive avoidance, OZP002 prevented scopolamine-induced learning deficits, in a NE-100 sensitive manner. Pre-administered IP before an ICV injection of amyloid A beta(25.35) peptide, a pharmacological model of Alzheimer's disease, OZP002 prevented the learning deficits induced by the peptide after one week in the Y-maze, passive avoidance and novel object tests. Biochemical analyses of the mouse hippocampi showed that OZP002 significantly decreased A beta(25.35)-induced increases in reactive oxygen species, lipid peroxidation, and increases in Bax, TNF alpha and IL-6 levels. Immunohistochemically, OZP002 prevented A beta(25.35)-induced reactive astrogliosis and microgliosis in the hippocampus. It also alleviated A beta(25.35)-induced decreases in synaptophysin level and choline acetyltransferase activity. Moreover, chronically administered in APPswe mice during 2 months, OZP002 prevented learning deficits (in all tests plus place learning in the water-maze) and increased biochemical markers. This study shows that a l PM with high neuropotective potential can be identified, combining pharmacological efficacy, selectivity and therapeutic safety, and identifies a novel promising compound, OZP002.