顺铂诱导的线粒体功能障碍与大鼠认知功能受损有关。
Cisplatin-induced mitochondrial dysfunction is associated with impaired cognitive function in rats.
作者信息
Lomeli Naomi, Di Kaijun, Czerniawski Jennifer, Guzowski John F, Bota Daniela A
机构信息
Department of Pathology & Laboratory Medicine, University of California Irvine, Irvine, CA, USA.
Department of Neurological Surgery, University of California Irvine, Irvine, CA, USA; Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA.
出版信息
Free Radic Biol Med. 2017 Jan;102:274-286. doi: 10.1016/j.freeradbiomed.2016.11.046. Epub 2016 Nov 28.
PURPOSE
Chemotherapy-related cognitive impairment (CRCI) is commonly reported following the administration of chemotherapeutic agents and comprises a wide variety of neurological problems. No effective treatments for CRCI are currently available. Here we examined the mechanisms involving cisplatin-induced hippocampal damage following cisplatin administration in a rat model and in cultured rat hippocampal neurons and neural stem/progenitor cells (NSCs). We also assessed the protective effects of the antioxidant, N-acetylcysteine in mitigating these damages.
EXPERIMENTAL DESIGN
Adult male rats received 6mg/kg cisplatin in the acute studies. In chronic studies, rats received 5mg/kg cisplatin or saline injections once per week for 4 weeks. N-acetylcysteine (250mg/kg/day) or saline was administered for five consecutive days during cisplatin treatment. Cognitive testing was performed 5 weeks after treatment cessation. Cisplatin-treated cultured hippocampal neurons and NSCs were examined for changes in mitochondrial function, oxidative stress production, caspase-9 activation, and neuronal dendritic spine density.
RESULTS
Acute cisplatin treatment reduced dendritic branching and spine density, and induced mitochondrial degradation. Rats receiving the chronic cisplatin regimen showed impaired performance in contextual fear conditioning, context object discrimination, and novel object recognition tasks compared to controls. Cisplatin induced mitochondrial DNA damage, impaired respiratory activity, increased oxidative stress, and activated caspase-9 in cultured hippocampal neurons and NSCs. N-acetylcysteine treatment prevented free radical production, ameliorated apoptotic cellular death and dendritic spine loss, and partially reversed the cisplatin-induced cognitive impairments.
CONCLUSIONS
Our results suggest that mitochondrial dysfunction and increased oxidative stress are involved in cisplatin-induced cognitive impairments. Therapeutic agents, such as N-acetylcysteine, may be effective in mitigating the deleterious effects of cisplatin.
目的
化疗相关认知障碍（CRCI）在化疗药物给药后普遍有报道，且包含多种神经问题。目前尚无针对CRCI的有效治疗方法。在此，我们在大鼠模型以及培养的大鼠海马神经元和神经干/祖细胞（NSC）中研究了顺铂给药后顺铂诱导海马损伤的机制。我们还评估了抗氧化剂N - 乙酰半胱氨酸在减轻这些损伤方面的保护作用。
实验设计
在急性研究中，成年雄性大鼠接受6mg/kg顺铂。在慢性研究中，大鼠每周接受一次5mg/kg顺铂或盐水注射，共4周。在顺铂治疗期间连续五天给予N - 乙酰半胱氨酸（250mg/kg/天）或盐水。在停止治疗5周后进行认知测试。对经顺铂处理的培养海马神经元和NSC进行线粒体功能、氧化应激产生、半胱天冬酶 - 9激活和神经元树突棘密度变化的检测。
结果
急性顺铂处理降低了树突分支和棘密度，并诱导线粒体降解。与对照组相比，接受慢性顺铂方案的大鼠在情境恐惧条件反射、情境物体辨别和新物体识别任务中的表现受损。顺铂诱导线粒体DNA损伤、呼吸活性受损、氧化应激增加，并在培养的海马神经元和NSC中激活半胱天冬酶 - 9。N - 乙酰半胱氨酸治疗可防止自由基产生，改善凋亡性细胞死亡和树突棘丢失，并部分逆转顺铂诱导的认知障碍。
结论
我们的结果表明，线粒体功能障碍和氧化应激增加与顺铂诱导的认知障碍有关。诸如N - 乙酰半胱氨酸之类的治疗药物可能有效减轻顺铂的有害影响。
Zotero 插件