The selective cyclooxygenase-2 inhibitor NS398 ameliorates cisplatin-induced impairments in mitochondrial and cognitive function.
The selective cyclooxygenase-2 inhibitor NS398 ameliorates cisplatin-induced impairments in mitochondrial and cognitive function.
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DOI：
10.3389/fnmol.2023.1295991
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发表时间：
2023
影响因子：
4.8
通讯作者：
Jang, Mi-Hyeon
中科院分区：
文献类型：
--
作者：
Rashid, Mohammad Abdur;Tang, Jason J.;Yoo, Ki-Hyun;Corujo-Ramirez, Ana;Oliveros, Alfredo;Kim, Sang Hoon;Ullah, Faheem;Altawell, Raad;Hawse, John R.;Cole, Peter D.;Jang, Mi-Hyeon
化学脑是一种对正在接受积极化疗的癌症患者以及化疗停止后的认知产生负面影响的病症。化疗引起的认知障碍（CICI）也被称为化疗引起的认知障碍（CICI），并已成为一种重要的医疗意外事件。没有治疗来改善这种状况，因此确定新的治疗策略，以防止CICI是癌症幸存者的极大兴趣。在CICI的研究方法中利用基于铂的化疗顺铂，我们确定了成年小鼠海马和来自诱导多能干细胞（iPSC）的人皮质神经元培养物中环氧合酶-2（考克斯-2）和前列腺素E2（PGE 2）的表达增加。值得注意的是，施用选择性考克斯-2抑制剂NS 398在体内预防CICI，而不负面影响顺铂的抗肿瘤功效或增强肿瘤生长。鉴于功能失调的线粒体生物能量学在CICI中起着重要作用，我们探讨了NS 398在顺铂诱导的人皮质线粒体缺陷中的作用。我们发现，顺铂显着降低线粒体膜电位（MMP），增加基质肿胀，导致嵴膜完整性的损失，损害ATP的生产，以及降低细胞活力和树突生长。在人皮层神经元中用NS 398预处理减弱了顺铂引起的线粒体功能障碍，同时改善了细胞存活和神经突形态发生。这些结果表明，异常的考克斯-2炎症通路可能有助于顺铂诱导的线粒体损伤和认知障碍。因此，考克斯-2信号传导可能代表了一种可行的治疗方法，以改善经历CICI的癌症幸存者的生活质量。
Chemobrain is a condition that negatively affects cognition in cancer patients undergoing active chemotherapy, as well as following chemotherapy cessation. Chemobrain is also known as chemotherapy-induced cognitive impairment (CICI) and has emerged as a significant medical contingency. There is no therapy to ameliorate this condition, hence identification of novel therapeutic strategies to prevent CICI is of great interest to cancer survivors. Utilizing the platinum-based chemotherapy cisplatin in an investigative approach for CICI, we identified increased expression of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) in the adult mouse hippocampus, and in human cortical neuron cultures derived from induced pluripotent stem cells (iPSCs). Notably, administration of NS398, a selective COX-2 inhibitor, prevented CICI in vivo without negatively affecting the antitumor efficacy of cisplatin or potentiating tumor growth. Given that dysfunctional mitochondrial bioenergetics plays a prominent role in CICI, we explored the effects of NS398 in cisplatin-induced defects in human cortical mitochondria. We found that cisplatin significantly reduces mitochondrial membrane potential (MMP), increases matrix swelling, causes loss of cristae membrane integrity, impairs ATP production, as well as decreases cell viability and dendrite outgrowth. Pretreatment with NS398 in human cortical neurons attenuated mitochondrial dysfunction caused by cisplatin, while improving cell survival and neurite morphogenesis. These results suggest that aberrant COX-2 inflammatory pathways may contribute in cisplatin-induced mitochondrial damage and cognitive impairments. Therefore, COX-2 signaling may represent a viable therapeutic approach to improve the quality of life for cancer survivors experiencing CICI.
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影响因子：
28.4
作者：
Kesler SR;Blayney DW
通讯作者：
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DOI：
10.1073/pnas.93.6.2317
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影响因子：
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