Mitochondrial and cognitive dysfunctions have long been associated with major depressive disorders (MDDs). Studies have shown that Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, possesses an antidepressant-like effect. Hence, the NMDA receptor can be a better therapeutic target for MDD. Therefore, the present study was designed to study the impact of Memantine on mitochondrial functional status and depression-like symptoms in the chronic unpredictable stress (CUS) model of depression. CUS for 28 days resulted in depression-like symptoms (as indicated by increased immobility time in the forced swim test) and a decline in the spatial learning and retention memory in the Morris water maze (MWM) test, which was prevented by Memantine (10 mg/kg/day) treatment. We observed elevated plasma corticosterone (CORT) levels, microdialysates glutamate concentration, and synaptosomal calcium (Ca²⁺) ion levels after 28 days of CUS. Memantine treatment prevented only increased plasma CORT and synaptosomal Ca²⁺ ion levels. Memantine treatment also restored CUS induced increase in oxidative stress parameters [increased neuronal nitric oxide synthase (nNOS) expression, nitric oxide (NO) levels, lipid peroxidation (LPO) and superoxide dismutase (SOD) activity], decrease in mitochondrial electron transport chain (ETC) enzymes activity and mitochondrial membrane potential (MMP). CUS also reduced the expression of cell survival genes, cyclic-AMP response element-binding protein (CREB), and brain-derived nerve growth factor (BDNF), which was reversed by treatment with Memantine. CUS, however, caused a non-significant decrease in the hippocampal adenosine triphosphate (ATP) levels and a non-significant increase in the expression of pro-apoptotic genes, Caspase 3, and the number of TUNEL positive cells, indicating that hippocampal mitochondrial dysfunction caused due to CUS was not severe enough to affect overall energy production, mitochondrial integrity, and cellular apoptosis status. Thus, Memantine treatment exerts an antidepressant-like effect by preventing CUS induced excitotoxicity, oxidative stress, and enhancing CUS induced decrease in mitochondrial functioning and expression of cell survival genes via upregulation of stress-responsive CREB/BDNF signaling.

线粒体和认知功能障碍长期以来一直与重度抑郁症（MDD）相关。研究表明，Memantine 是一种 N-甲基-D-天冬氨酸 (NMDA) 受体拮抗剂，具有类似抗抑郁的作用。因此，NMDA受体可以成为MDD更好的治疗靶点。因此，本研究旨在研究美金刚对抑郁症慢性不可预测应激（CUS）模型中线粒体功能状态和抑郁样症状的影响。 28 天的 CUS 导致抑郁样症状（如强迫游泳测试中不动时间增加所示）以及莫里斯水迷宫 (MWM) 测试中空间学习和保留记忆的下降，美金刚可以预防这种症状（10毫克/公斤/天）治疗。我们观察到 CUS 28 天后血浆皮质酮 (CORT) 水平、微透析液谷氨酸浓度和突触体钙 (Ca ²⁺ ) 离子水平升高。美金刚治疗仅阻止血浆 CORT 和突触体 Ca ²⁺离子水平升高。美金刚治疗还恢复了 CUS 诱导的氧化应激参数增加 [增加神经元一氧化氮合酶 (nNOS) 表达、一氧化氮 (NO) 水平、脂质过氧化 (LPO) 和超氧化物歧化酶 (SOD) 活性]、线粒体电子传递链减少。 ETC）酶活性和线粒体膜电位（MMP）。 CUS 还降低了细胞存活基因、环磷酸腺苷反应元件结合蛋白 (CREB) 和脑源性神经生长因子 (BDNF) 的表达，美金刚治疗可逆转这种情况。 然而，CUS 导致海马三磷酸腺苷 (ATP) 水平非显着降低，促凋亡基因 Caspase 3 的表达和 TUNEL 阳性细胞数量非显着增加，表明海马线粒体功能障碍由 CUS 引起的损伤还没有严重到影响整体能量产生、线粒体完整性和细胞凋亡状态。因此，美金刚治疗通过预防 CUS 诱导的兴奋性毒性、氧化应激，并通过上调应激反应性 CREB/BDNF 信号传导增强 CUS 诱导的线粒体功能和细胞存活基因表达的下降，从而发挥抗抑郁样作用。