Neuroprotection in non-transgenic and transgenic mouse models of Alzheimer's disease by positive modulation of σ1 receptors

Abstract

The sigma-1 (σ₁) 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 σ₁ agonist molecules activate the protein and act behaviorally as antidepressant, anti-amnesic and neuroprotective agents. Recently, several chemically unrelated molecules were shown to be σ₁ receptor positive modulators (PMs), with some of them a clear demonstration of their allostericity. We here examined whether a σ₁ 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 σ₁ PM. OZP002 does not bind σ₁ sites but induces σ₁ effects in vivo and boosts σ₁ agonist activity. OZP002 was antidepressant in the forced swim test and its effect was blocked by the σ₁ antagonist NE-100 or in σ₁ receptor knockout mice. It potentiated the antidepressant effect of the σ₁ 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 σ₁ PM with high neuropotective potential can be identified, combining pharmacological efficacy, selectivity and therapeutic safety, and identifies a novel promising compound, OZP002.

Keywords: Alzheimer's disease; Anti-amnesic; Antidepressant; Neuroprotection; OZP002; σ(1) Receptor.