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

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.
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