Chemotherapy-associated neurotoxicity is one of the principal side-effects for doxorubicin (DOX)-treated cancer patients. Despite its poor-penetration across the blood–brain barrier (BBB), DOX is linked to the induction of oxidative stress and neuroinflammation. Berberine (BEB) is a natural polyphenolic alkaloid, which exhibits unique antioxidant activity and anti-inflammatory potential. The present study was performed to investigate the neuroprotective potential of BEB in a rodent model of DOX-induced neurotoxicity. Neurotoxicity was induced in rats via a single acute dose of DOX (20 mg/kg/week, i.p.). BEB was administered at 50 mg/kg/day orally for 10 days before and 4 days after DOX administration. Brain acetylcholinesterase (AChE) activities were evaluated. Oxidative stress was investigated via the colorimetric determination of lipid peroxides, glutathione reduced (GSH) contents and catalase (CAT) activities in the brain tissue. In addition, DOX-induced genotoxicity was evaluated using comet assay. DOX produced a significant elevation in AChE activities. Additionally, DOX provoked oxidative stress as evidenced from the significant elevation in lipid peroxidation along with depletion in GSH contents and CAT activities. Moreover, DOX resulted in neuroinflammation as indicated by the elevation of pro-inflammatory mediator glial fibrillary acid protein (GFAP), as well as, the pro-apoptotic nuclear factor kappa B (NF-κB) and caspase-3 in brain tissue. Co-treatment with BEB significantly counteracted DOX-induced oxidative stress, neuroinflammation and genotoxicity. Histopathological and immunohistochemical examination supported the biochemical results. BEB demonstrated neuroprotective potential through exerting cholinergic, anti-oxidative, genoprotective, anti-inflammatory, and anti-apoptotic activities. Our findings present BEB as a promising “pre-clinical” neuroprotective agent against DOX-induced neurotoxicity during anti-neoplastic therapy.

化疗相关的神经毒性是阿霉素 (DOX) 治疗癌症患者的主要副作用之一。尽管 DOX 穿过血脑屏障 (BBB) 的渗透性较差，但它与氧化应激和神经炎症的诱导有关。小檗碱 (BEB) 是一种天然多酚生物碱，具有独特的抗氧化活性和抗炎潜力。本研究旨在研究 BEB 在 DOX 诱导的神经毒性啮齿动物模型中的神经保护潜力。通过单次急性剂量的 DOX（20 mg/kg/周，腹膜内注射）诱导大鼠神经毒性。在 DOX 给药前 10 天和给药后 4 天，以 50 mg/kg/天的剂量口服 BEB。评估脑乙酰胆碱酯酶（AChE）活性。通过比色测定脂质过氧化物来研究氧化应激，脑组织中还原型谷胱甘肽（GSH）含量和过氧化氢酶（CAT）活性。此外，使用彗星试验评估了 DOX 诱导的遗传毒性。DOX 显着提高了 AChE 活性。此外，DOX 会引发氧化应激，脂质过氧化显着升高以及 GSH 含量和 CAT 活性的消耗证明了这一点。此外，DOX 会导致神经炎症，表现为脑组织中促炎介质胶质纤维酸性蛋白 (GFAP) 以及促凋亡核因子 kappa B (NF-κB) 和 caspase-3 的升高。与 BEB 联合治疗可显着抵消 DOX 诱导的氧化应激、神经炎症和遗传毒性。组织病理学和免疫组织化学检查支持生化结果。BEB 通过发挥胆碱能、抗氧化、基因保护、抗炎和抗凋亡活性表现出神经保护潜力。我们的研究结果表明，BEB 是一种很有前途的“临床前”神经保护剂，可对抗抗肿瘤治疗期间 DOX 引起的神经毒性。