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.

化疗会导致不良的长期神经系统后遗症、化疗引起的认知障碍（CICI）或癌症幸存者的化疗脑。程序性细胞死亡（PCD）的激活被认为与化学脑的发育和进展有关。神经元凋亡在化疗脑实验模型中已得到广泛认可，但对化疗反应的 PCD 的替代形式知之甚少。乙酰胆碱受体（AChR）的激活正在成为减轻与神经变性相关的多种神经元死亡的有希望的靶标。因此，本研究旨在探讨AChR激动剂对认知功能的治疗能力以及多种PCD对抗化疗神经毒性的分子标志。为了建立化学脑模型，雄性 Wistar 大鼠被分配通过腹腔注射接受六剂阿霉素（DOX：3 mg/kg）。 DOX 治疗的大鼠接受 a7nAChR 激动剂（PNU-282987：3 mg/kg/天）、mAChR 激动剂（氨甲酰甲胆碱：12 mg/kg/天）或两者联合治疗。 DOX 给药通过神经炎症、神经胶质激活、突触/血脑屏障完整性降低、线粒体 ROS 解毒能力缺陷和动态失衡导致认知功能受损。 DOX 损伤还介导 Tau 过度磷酸化，同时诱导各种 PCD，包括海马细胞凋亡、坏死性凋亡和细胞焦亡。同时使用 PNU-282987、氨甲酰甲胆碱或两者的组合进行治疗，可有效减轻 DOX 治疗大鼠的神经炎症、线粒体稳态失衡和 Tau 过度磷酸化，从而抑制过度细胞凋亡、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学脑。