Division of Pharmacology, Institute of Pharmaceutical Research, GLA University, Mathura, 281 406, India.
Division of Pharmacology, Institute of Pharmaceutical Research, GLA University, Mathura, 281 406, India.
Neurochem Int. 2019 Sep;128:39-49. doi: 10.1016/j.neuint.2019.04.006. Epub 2019 Apr 17.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, disorientation and gradual deterioration of intellectual ability. In the pharmacotherapy of AD, the mitochondrial protective activity of Exendin-4 in experimental studies is yet to be established though its effectiveness is demonstrated in these patients. Therefore, the mitochondria protective activity of Exendin-4 (5 μg/kg, i.p.) was investigated in hippocampus and pre-frontal cortex (PFC) of AD-like animals. The amyloid beta (Aβ) was injected through bilateral intracerebroventricular route into lateral ventricles to induce AD-like manifestations in the male rats. Exendin-4 significantly attenuated Aβ-induced memory-deficits in the Morris water maze and Y-maze test protocols. Exendin-4 significantly decreased Aβ-induced increase in the level of Aβ in both brain regions. Exendin-4 significantly increased Aβ-induced decrease in acetylcholine level and activity of cholineacetyl transferase in all brain regions. Moreover, Exendin-4 significantly decreased Aβ-induced increase in the activity of acetylcholinestrase in both the brain regions. E4 significantly increased Aβ-induced decrease in mitochondrial function, integrity, respiratory control rate and ADP/O in all brain regions. Further, Exendin-4 significantly decreased Aβ-induced increase in the mitochondrial complex enzyme-I, IV and V activities in all brain regions. Furthermore, Exendin-4 significantly increased Aβ-induced decrease in the level of phosphorylated Akt and the ratio of phosphorylated Akt to Akt in both brain regions. However, LY294002 diminished the therapeutic effects of Exendin-4 on behavioral, biochemical and molecular observations in AD-like animals. Pearson's analysis showed that the attributes of mitochondrial dysfunction (MMP and RCR) exhibited significant correlation to the loss in memory formation, level of Aβ and cholinergic dysfunction in these animals. Thus, it can be speculated that Exendin-4 may mitigate AD-like manifestations including mitochondrial toxicity perhaps through PI3K/Akt-mediated pathway in the experimental animals. Hence, Exendin-4 could be a potential therapeutic alternative candidate in the management of AD.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征是记忆力减退、定向障碍和智力逐渐恶化。在 AD 的药物治疗中，尽管已有研究证明 Exendin-4 对这些患者有效，但在实验研究中其线粒体保护活性尚未得到证实。因此，研究人员在类似 AD 的动物的海马体和前额叶皮层（PFC）中研究了 Exendin-4 的线粒体保护活性。通过双侧侧脑室脑室内注射淀粉样β（Aβ），在雄性大鼠中诱导出类似 AD 的表现。Exendin-4 显著减轻了 Morris 水迷宫和 Y 迷宫测试方案中 Aβ 诱导的记忆缺陷。Exendin-4 显著降低了两个脑区中 Aβ 诱导的 Aβ 水平升高。Exendin-4 显著增加了 Aβ 诱导的所有脑区中乙酰胆碱水平和胆碱乙酰转移酶活性的降低。此外，Exendin-4 显著降低了两个脑区中 Aβ 诱导的乙酰胆碱酯酶活性增加。E4 显著增加了所有脑区中 Aβ 诱导的线粒体功能、完整性、呼吸控制率和 ADP/O 降低。此外，Exendin-4 显著降低了所有脑区中 Aβ 诱导的线粒体复合物酶-I、IV 和 V 活性增加。此外，Exendin-4 显著增加了 Aβ 诱导的两个脑区中磷酸化 Akt 水平和磷酸化 Akt 与 Akt 比值降低。然而，LY294002 减弱了 Exendin-4 在类似 AD 动物的行为、生化和分子观察中的治疗作用。Pearson 分析显示，线粒体功能障碍的特征（MMP 和 RCR）与这些动物的记忆形成丧失、Aβ 水平和胆碱能功能障碍显著相关。因此，可以推测 Exendin-4 可能通过 PI3K/Akt 介导的途径减轻包括线粒体毒性在内的类似 AD 的表现，在实验动物中。因此，Exendin-4 可能是 AD 管理的潜在治疗选择。
