Targeting p38/JNK MAPK to ameliorate cisplatin-induced adverse sequelae on the nervous system

化疗相关认知损害（CRCI，chemobrain）、化疗诱导的周围神经病变 （CIPN）和步态变化是用铂剂治疗癌症的使人衰弱的副作用（例如，顺铂）， 紫杉烷和长春花生物碱。顺铂是一种广泛用于治疗卵巢恶性肿瘤的化疗药物。 超过70%的女性报告在治疗期间或完成后经历CRCI、CIPN和/或福尔斯， 他们的生活质量。这些神经毒性损伤也会影响顺铂的治疗， 疾病进展。目前，没有FDA批准的用于治疗CRCI的临床干预措施， CIPN。从机制上讲，顺铂诱导的神经元毒性来源于核和线粒体DNA损伤， 和氧化应激，其诱导丝裂原活化蛋白激酶（MAPK），p38 MAPK 和c-Jun N-末端激酶（JNK），导致神经元凋亡。我们的初步数据显示， 小分子抑制剂的药理学抑制，即，neflamapimod用于p38 MAPK，SP 600125用于 JNK阻止顺铂诱导的树突棘分支和密度的减少。根据这些数据，我们 假设p38 MAPK/JNK通路抑制将阻止顺铂诱导的神经元凋亡， 细胞凋亡和损伤，导致认知障碍、步态改变和神经性疾病的减轻。 与CRCI和CIPN相关的疼痛。在本项目中，我们打算确定是否：（1）顺铂诱导的p38 MAPK/JNK信号转导是结构和功能神经元损伤的基础，使用体外药理学方法 抑制和siRNA沉默;（2）neflamapimod和SP 600125预防顺铂诱导神经病变和步态 C57 BL/6小鼠中ID 8同基因上皮性卵巢癌和转基因乳腺癌中的改变 FVBN小鼠模型C3 TAg;（3）顺铂诱导的神经毒性可通过抑制p38 MAPK/JNK而减弱 而不影响其抗癌活性。我们的方法包括体外分析2个单独的神经元细胞 线，使用CIPN的感觉测试的行为分析，认知障碍的测试，和新的 MouseWalker使用两种小鼠癌症模型在雌性小鼠中进行步态改变。拟议的研究将 证明了p38 MAPK和JNK在顺铂诱导的CRCI/CIPN中的作用，以及p38 MAPK和JNK在顺铂诱导的CRCI/CIPN中的翻译潜力。 治疗CRCI和CIPN的新策略。由于健康方面的差异，妇女遭受的不成比例的 癌症和疼痛相关的治疗。因此，在雌性小鼠中测试我们的假设有望 显著推进对顺铂诱导的神经毒性副作用的理解和治疗， 女性癌症患者的生活质量。尽管如此，我们预计这些发现也适用于顺铂- 在男性和卵巢癌和乳腺癌以外的其他癌症中诱导神经毒性。

Chemotherapy-related cognitive impairment (CRCI, chemobrain), chemotherapy-induced peripheral neuropathy (CIPN) and gait changes are debilitating side-effects of cancer treatment with platinum agents (e.g., cisplatin), taxanes, and vinca alkaloids. Cisplatin is widely used as a chemotherapeutic agent to treat ovarian malignancies. Over 70% of women report experiencing CRCI, CIPN and/or falls during treatment or after completion, impairing their quality of life. These neurotoxic impairments can also compromise treatment with cisplatin, influencing disease progression. Currently, there are no FDA-approved clinical interventions for the treatment of CRCI and CIPN. Mechanistically, cisplatin-induced neuronal toxicity derives from nuclear and mitochondrial DNA damage, and oxidative stress, which induce the activation of the mitogen-activated protein kinases (MAPK), p38MAPK and c-Jun N-terminal kinase (JNK), leading to neuronal apoptosis. Our preliminary data show that in vitro pharmacological inhibition with small molecule inhibitors, i.e., neflamapimod for p38MAPK and SP600125 for JNK, prevents cisplatin-induced reduction in dendritic spine branching and density. Based on these data, we hypothesize that inhibition of the p38MAPK/JNK pathways will prevent cisplatin-induced neuronal apoptosis and damage, leading to attenuation of cognitive impairments, gait changes, and neuropathic pain associated with CRCI and CIPN. In this project, we propose to determine if: (1) cisplatin-induced p38 MAPK/JNK signaling underlies structural and functional neuronal damage, using in vitro pharmacological inhibition and siRNA silencing; (2) neflamapimod and SP600125 prevent cisplatin-induced neuropathy and gait alterations in the ID8 syngeneic epithelial ovarian cancer in C57BL/6 mice and the transgenic breast cancer model C3TAg in FVBN mice; and (3) cisplatin-induced neurotoxicity is attenuated by p38MAPK/JNK inhibition without compromising its anti-cancer activity. Our Approach includes in vitro analysis of 2 separate neuronal cell lines, behavioral analysis using sensory testing for CIPN, testing of cognitive impairment, and novel MouseWalker for gait changes in female mice using the two mouse cancer models. The proposed studies will demonstrate the role of the p38MAPK and JNK in cisplatin induced CRCI/CIPN, and translational potential for novel strategies to treat CRCI and CIPN. Due to health disparities, women suffer more disproportionately from cancer and pain-related treatment than men. Therefore, testing our hypothesis in female mice is expected to significantly advance the understanding and treatment of cisplatin-induced neurotoxic side effects and improve the quality of life for women with cancer. Nevertheless, we expect that these findings may also apply to cisplatin- induced neurotoxicity in males and to other cancers than ovarian and breast cancers.