Ongnok Benjamin, Khuanjing Thawatchai, Chunchai Titikorn, Kerdphoo Sasiwan, Jaiwongkam Thidarat, Chattipakorn Nipon, Chattipakorn Siriporn C
Neuroelectrophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Chiang Mai University, Chiang Mai 50200, Thailand.
Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Chiang Mai University, Chiang Mai 50200, Thailand.
Biochim Biophys Acta Mol Basis Dis. 2021 Jan 1;1867(1):165975. doi: 10.1016/j.bbadis.2020.165975. Epub 2020 Sep 18.
Cardiac ischemia/reperfusion (I/R) injury induces brain pathology. Donepezil, a well-known acetylcholine esterase (AChE) inhibitor, has been proven to exert neuroprotective effects against several neurodegenerative diseases. However, the comprehensive mechanism regarding the therapeutic potential of donepezil on the brain under cardiac I/R injury remains obscure. Here, we hypothesized that treatment with donepezil ameliorates brain pathology following cardiac I/R injury by decreasing blood brain barrier (BBB) breakdown, oxidative stress, neuroinflammation, mitochondrial dysfunction, mitochondrial dynamics imbalance, microglial activation, amyloid-beta (Aβ) accumulation, neuronal apoptosis, and dendritic spine loss. Forty-eight adult male Wistar rats were subjected to surgery for cardiac I/R injury. Then, rats were randomly divided into four groups to receive either (1) saline (vehicle group), donepezil 3 mg/kg via intravenously administered (2) before ischemia (pretreatment group), (3) during ischemia (ischemia group), or (4) at the onset of reperfusion (reperfusion group). At the end of cardiac I/R paradigm, the brains were evaluated for BBB breakdown, brain inflammation, oxidative stress, mitochondrial function, mitochondrial dynamics, microglial morphology, Aβ production, neuronal apoptosis, and dendritic spine density. Administration of donepezil at all time points equally showed an attenuation of brain damage in response to cardiac I/R injury, as indicated by increased expression of BBB junction protein, reduced brain inflammation and oxidative stress, improved mitochondrial function and mitochondrial dynamics, and alleviated Aβ accumulation and microglial activation, resulting in protection of neuronal apoptosis and preservation of dendritic spine number. These findings suggest that donepezil potentially protects brain pathology caused by cardiac I/R injury regardless the timing of treatment.
心脏缺血/再灌注（I/R）损伤会诱发脑部病变。多奈哌齐是一种著名的乙酰胆碱酯酶（AChE）抑制剂，已被证明对多种神经退行性疾病具有神经保护作用。然而，关于多奈哌齐在心脏I/R损伤情况下对脑部治疗潜力的全面机制仍不清楚。在此，我们假设多奈哌齐治疗可通过减少血脑屏障（BBB）破坏、氧化应激、神经炎症、线粒体功能障碍、线粒体动力学失衡、小胶质细胞激活、淀粉样β蛋白（Aβ）积累、神经元凋亡和树突棘丢失来改善心脏I/R损伤后的脑部病变。48只成年雄性Wistar大鼠接受了心脏I/R损伤手术。然后，将大鼠随机分为四组，分别接受以下处理：（1）生理盐水（载体组），（2）缺血前静脉注射3 mg/kg多奈哌齐（预处理组），（3）缺血期间（缺血组），或（4）再灌注开始时（再灌注组）。在心脏I/R实验结束时，对大脑进行评估，检测BBB破坏、脑炎症、氧化应激、线粒体功能、线粒体动力学、小胶质细胞形态、Aβ产生、神经元凋亡和树突棘密度。在所有时间点给予多奈哌齐均同样显示出对心脏I/R损伤引起的脑损伤有减轻作用，表现为BBB连接蛋白表达增加、脑炎症和氧化应激减轻、线粒体功能和线粒体动力学改善、Aβ积累和小胶质细胞激活减轻，从而保护神经元凋亡并保留树突棘数量。这些发现表明，无论治疗时机如何，多奈哌齐都可能保护心脏I/R损伤引起的脑部病变。
