Neuroelectrophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Mueang Chiang Mai, 50200, Chiang Mai, Thailand.
Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Mueang Chiang Mai, 50200, Chiang Mai, Thailand.
Mol Neurobiol. 2024 Nov;61(11):8831-8850. doi: 10.1007/s12035-024-04145-0. Epub 2024 Apr 3.
Chemotherapy causes undesirable long-term neurological sequelae, chemotherapy-induced cognitive impairment (CICI), or chemobrain in cancer survivors. Activation of programmed cell death (PCD) has been proposed to implicate in the development and progression of chemobrain. Neuronal apoptosis has been extensively recognized in experimental models of chemobrain, but little is known about alternative forms of PCD in response to chemotherapy. Activation of acetylcholine receptors (AChRs) is emerging as a promising target in attenuating a wide variety of the neuronal death associated with neurodegeneration. Thus, this study aimed to investigate the therapeutic capacity of AChR agonists on cognitive function and molecular hallmarks of multiple PCD against chemotherapy neurotoxicity. To establish the chemobrain model, male Wistar rats were assigned to receive six doses of doxorubicin (DOX: 3 mg/kg) via intraperitoneal injection. The DOX-treated rats received either an a7nAChR agonist (PNU-282987: 3 mg/kg/day), mAChR agonists (bethanechol: 12 mg/kg/day), or the two as a combined treatment. DOX administration led to impaired cognitive function via neuroinflammation, glial activation, reduced synaptic/blood-brain barrier integrity, defective mitochondrial ROS-detoxifying capacity, and dynamic imbalance. DOX insult also mediated hyperphosphorylation of Tau and simultaneously induced various PCD, including apoptosis, necroptosis, and pyroptosis in the hippocampus. Concomitant treatment with either PNU-282987, bethanechol, or a combination of the two potently attenuated neuroinflammation, mitochondrial dyshomeostasis, and Tau hyperphosphorylation, thereby suppressing excessive apoptosis, necroptosis, and pyroptosis and improving cognitive function in DOX-treated rats. Our findings suggest that activation of AChRs using their agonists effectively protected against DOX-induced neuronal death and chemobrain.
化疗会导致癌症幸存者出现不良的长期神经后遗症、化疗引起的认知障碍（CICI）或化疗脑。程序性细胞死亡（PCD）的激活被认为与化疗脑的发展和进展有关。神经元凋亡已在化疗脑的实验模型中得到广泛认可，但对化疗引起的PCD的其他形式知之甚少。乙酰胆碱受体（AChR）的激活作为减轻与神经退行性变相关的多种神经元死亡的有前途的靶点而出现。因此，本研究旨在研究 AChR 激动剂对认知功能和多种 PCD 的分子特征的治疗能力，以对抗化疗的神经毒性。为了建立化疗脑模型，雄性 Wistar 大鼠被分配接受六剂多柔比星（DOX：3mg/kg）腹腔注射。DOX 处理的大鼠接受 a7nAChR 激动剂（PNU-282987：3mg/kg/天）、mAChR 激动剂（氨甲酰胆碱：12mg/kg/天）或两者联合治疗。DOX 给药通过神经炎症、神经胶质激活、减少突触/血脑屏障完整性、线粒体 ROS 解毒能力受损和动态失衡导致认知功能障碍。DOX 损伤还介导 Tau 的过度磷酸化，并同时诱导各种 PCD，包括海马中的凋亡、坏死性凋亡和细胞焦亡。同时使用 PNU-282987、氨甲酰胆碱或两者的组合可有效减弱神经炎症、线粒体功能障碍和 Tau 过度磷酸化，从而抑制 DOX 处理的大鼠中过度的凋亡、坏死性凋亡和细胞焦亡，并改善认知功能。我们的研究结果表明，使用 AChR 激动剂激活 AChR 可有效防止 DOX 诱导的神经元死亡和化疗脑。
