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

Abstract

The sigma-1 (σ 1 ) receptor is an endoplasmic reticulum (ER) chaperone protein, enriched in mitochondria-associated membranes. Its activation triggers physiological responses to ER stress and modulate Ca 2+ mobilization in mitochondria. Small σ 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 σ 1 receptor positive modulators (PMs), with some of them a clear demonstration of their allostericity. We here examined whether a σ 1 PM also shows neuroprotective potentials in pharmacological and genetic models of Alzheimer's disease (AD). For this aim, we describe (±)-2-(3-chlorophenyl)-3,3,5,5-tetramethyl-2-oxo-[1,4,2]-oxazaphosphinane (OZP002) as a novel σ 1 PM. OZP002 does not bind σ 1 sites but induces σ 1 effects in vivo and boosts σ 1 agonist activity. OZP002 was antidepressant in the forced swim test and its effect was blocked by the σ 1 antagonist NE-100 or in σ 1 receptor knockout mice. It potentiated the antidepressant effect of the σ 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 Aβ 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 Aβ 25-35 -induced increases in reactive oxygen species, lipid peroxidation, and increases in Bax, TNFα and IL-6 levels. Immunohistochemically, OZP002 prevented Aβ 25-35 -induced reactive astrogliosis and microgliosis in the hippocampus. It also alleviated Aβ 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 σ 1 PM with high neuropotective potential can be identified, combining pharmacological efficacy, selectivity and therapeutic safety, and identifies a novel promising compound, OZP002.