Inserm U 710, University of Montpellier 2 Montpellier, France ; Amylgen, Montferrier-sur-Lez France.
Inserm U 955, Team 03, Créteil France ; Faculty of Medicine, Université Paris-Est, Unité Mixte de Recherche S955, Université Paris-Est Créteil Val-de-Marne Créteil, France.
Front Cell Neurosci. 2015 Jan 20;8:463. doi: 10.3389/fncel.2014.00463. eCollection 2014.
Alzheimer's disease (AD), the most prevalent dementia in the elderly, is characterized by progressive synaptic and neuronal loss. Mitochondrial dysfunctions have been consistently reported as an early event in AD and appear before Aβ deposition and memory decline. In order to define a new neuroprotectant strategy in AD targeting mitochondrial alterations, we develop tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine (ANAVEX2-73, AE37), a mixed muscarinic receptor ligand and a sigma-1 receptor (σ1R) agonist. We previously reported that ANAVEX2-73 shows anti-amnesic and neuroprotective activities in mice injected intracerebroventricular (ICV) with oligomeric amyloid-β25-35 peptide (Aβ25-35). The σ1R is present at mitochondria-associated endoplasmic reticulum (ER) membranes, where it acts as a sensor/modulator of ER stress responses and local Ca(2+) exchanges with the mitochondria. We therefore evaluated the effect of ANAVEX2-73 and PRE-084, a reference σ1R agonist, on preservation of mitochondrial integrity in Aβ25-35-injected mice. In isolated mitochondria from hippocampus preparations of Aβ25-35 injected animals, we measured respiration rates, complex activities, lipid peroxidation, Bax/Bcl-2 ratios and cytochrome c release into the cytosol. Five days after Aβ25-35 injection, mitochondrial respiration in mouse hippocampus was altered. ANAVEX2-73 (0.01-1 mg/kg IP) restored normal respiration and PRE-084 (0.5-1 mg/kg IP) increased respiration rates. Both compounds prevented Aβ25-35-induced increases in lipid peroxidation levels, Bax/Bcl-2 ratio and cytochrome c release into the cytosol, all indicators of increased toxicity. ANAVEX2-73 and PRE-084 efficiently prevented the mitochondrial respiratory dysfunction and resulting oxidative stress and apoptosis. The σ1R, targeted selectively or non-selectively, therefore appears as a valuable target for protection against mitochondrial damages in AD.
阿尔茨海默病（AD）是老年人中最常见的痴呆症，其特征是突触和神经元进行性丧失。线粒体功能障碍一直被认为是 AD 的早期事件，并且出现在 Aβ沉积和记忆下降之前。为了确定针对线粒体改变的 AD 的新神经保护策略，我们开发了四氢-N，N-二甲基-2,2-二苯基-3-呋喃甲胺（ANAVEX2-73，AE37），一种混合毒蕈碱受体配体和 sigma-1 受体（σ1R）激动剂。我们之前报道过，ANAVEX2-73 对注射寡聚淀粉样β25-35 肽（Aβ25-35）的小鼠具有抗健忘和神经保护作用。σ1R 存在于线粒体相关内质网（ER）膜上，作为 ER 应激反应的传感器/调节剂，并与线粒体进行局部 Ca（2+）交换。因此，我们评估了 ANAVEX2-73 和 PRE-084（一种参考 σ1R 激动剂）对 Aβ25-35 注射小鼠中线粒体完整性的保护作用。在从 Aβ25-35 注射动物的海马制备物中分离的线粒体中，我们测量了呼吸速率，复合物活性，脂质过氧化，Bax/Bcl-2 比值和细胞色素 c 向细胞质中的释放。在 Aβ25-35 注射后 5 天，小鼠海马中的线粒体呼吸发生改变。ANAVEX2-73（0.01-1 mg/kg IP）恢复了正常的呼吸，而 PRE-084（0.5-1 mg/kg IP）则增加了呼吸速率。这两种化合物均防止了 Aβ25-35 诱导的脂质过氧化水平，Bax/Bcl-2 比值和细胞色素 c 向细胞质中的释放增加，所有这些均表明毒性增加。ANAVEX2-73 和 PRE-084 有效地防止了线粒体呼吸功能障碍以及由此产生的氧化应激和细胞凋亡。因此，选择性或非选择性靶向 σ1R 似乎是防止 AD 中线粒体损伤的有价值的靶标。
