MMDN, Univ Montpellier, INSERM, EPHE, UMR-S1198, Montpellier, France.
Institut Charles Gerhardt, ENSCM, CNRS, UMR5253, Montpellier, France.
Pharmacol Res. 2019 Jun;144:315-330. doi: 10.1016/j.phrs.2019.04.026. Epub 2019 Apr 29.
The sigma-1 (σ) receptor is an endoplasmic reticulum (ER) chaperone protein, enriched in mitochondria-associated membranes. Its activation triggers physiological responses to ER stress and modulate Ca mobilization in mitochondria. Small σ 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 receptor positive modulators (PMs), with some of them a clear demonstration of their allostericity. We here examined whether a σ 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 PM. OZP002 does not bind σ sites but induces σ effects in vivo and boosts σ agonist activity. OZP002 was antidepressant in the forced swim test and its effect was blocked by the σ antagonist NE-100 or in σ receptor knockout mice. It potentiated the antidepressant effect of the σ 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 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-induced increases in reactive oxygen species, lipid peroxidation, and increases in Bax, TNFα and IL-6 levels. Immunohistochemically, OZP002 prevented Aβ-induced reactive astrogliosis and microgliosis in the hippocampus. It also alleviated Aβ-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 PM with high neuropotective potential can be identified, combining pharmacological efficacy, selectivity and therapeutic safety, and identifies a novel promising compound, OZP002.
σ1（σ）受体是内质网（ER）伴侣蛋白，富含在线粒体相关膜中。其激活引发 ER 应激的生理反应，并调节线粒体中的钙动员。小 σ 激动剂分子激活该蛋白，并表现出抗抑郁、抗健忘和神经保护作用。最近，一些化学上无关的分子被证明是 σ 受体正向调节剂（PMs），其中一些分子清楚地证明了它们的变构性。我们在这里检查了一种 σ PM 是否在阿尔茨海默病（AD）的药理学和遗传学模型中也具有神经保护潜力。为此，我们描述了（±）-2-（3-氯苯基）-3,3,5,5-四甲基-2-氧代-[1,4,2]-氧杂膦杂环戊烷（OZP002）作为一种新型的 σ PM。OZP002 不与 σ 结合，但在体内诱导 σ 效应并增强 σ 激动剂的活性。OZP002 在强迫游泳试验中具有抗抑郁作用，其作用被 σ 拮抗剂 NE-100 或在 σ 受体敲除小鼠中阻断。它增强了 σ 激动剂 igmesine 的抗抑郁作用。在 Y 迷宫交替或被动回避测试中，OZP002 以 NE-100 敏感的方式预防 scopolamine 诱导的学习缺陷。在淀粉样 Aβ肽的 ICV 注射前预先 IP 给药，这是阿尔茨海默病的药理学模型，OZP002 可防止一周后在 Y 迷宫、被动回避和新物体测试中肽引起的学习缺陷。对小鼠海马的生化分析表明，OZP002 可显著降低 Aβ 诱导的活性氧、脂质过氧化、Bax、TNFα 和 IL-6 水平的增加。免疫组织化学分析显示，OZP002 可预防 Aβ 诱导的海马反应性星形胶质细胞增生和小胶质细胞增生。它还缓解了 Aβ 诱导的突触小体蛋白水平和胆碱乙酰转移酶活性的降低。此外，在 APPswe 小鼠中慢性给药 2 个月，OZP002 可预防学习缺陷（所有测试加上水迷宫中的位置学习）并增加生化标志物。这项研究表明，可以识别具有高神经保护潜力的 σ PM，结合药理学功效、选择性和治疗安全性，并确定了一种新的有前途的化合物 OZP002。
