Wardill Hannah R, Mander Kimberley A, Van Sebille Ysabella Z A, Gibson Rachel J, Logan Richard M, Bowen Joanne M, Sonis Stephen T
School of Medicine, University of Adelaide, South Australia.
Centre for Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, South Australia.
Int J Cancer. 2016 Dec 15;139(12):2635-2645. doi: 10.1002/ijc.30252. Epub 2016 Jul 15.
Neurotoxicity is a common side effect of chemotherapy treatment, with unclear molecular mechanisms. Clinical studies suggest that the most frequent neurotoxic adverse events affect memory and learning, attention, concentration, processing speeds and executive function. Emerging preclinical research points toward direct cellular toxicity and induction of neuroinflammation as key drivers of neurotoxicity and subsequent cognitive impairment. Emerging data now show detectable levels of some chemotherapeutic agents within the CNS, indicating potential disruption of blood brain barrier integrity or transport mechanisms. Blood brain barrier disruption is a key aspect of many neurocognitive disorders, particularly those characterized by a proinflammatory state. Importantly, many proinflammatory mediators able to modulate the blood brain barrier are generated by tissues and organs that are targets for chemotherapy-associated toxicities. This review therefore aims to explore the hypothesis that peripherally derived inflammatory cytokines disrupt blood brain barrier permeability, thereby increasing direct access of chemotherapeutic agents into the CNS to facilitate neuroinflammation and central neurotoxicity.
神经毒性是化疗常见的副作用，其分子机制尚不清楚。临床研究表明，最常见的神经毒性不良事件会影响记忆、学习、注意力、专注力、处理速度和执行功能。新出现的临床前研究指出，直接的细胞毒性和神经炎症的诱导是神经毒性及随后认知障碍的关键驱动因素。新数据显示，中枢神经系统内可检测到某些化疗药物的水平，这表明血脑屏障完整性或转运机制可能受到破坏。血脑屏障破坏是许多神经认知障碍的一个关键方面，尤其是那些以促炎状态为特征的障碍。重要的是，许多能够调节血脑屏障的促炎介质是由化疗相关毒性的靶组织和器官产生的。因此，本综述旨在探讨以下假说：外周来源的炎性细胞因子会破坏血脑屏障的通透性，从而增加化疗药物进入中枢神经系统的直接途径，促进神经炎症和中枢神经毒性。
