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

化疗相关的认知障碍(CRCI、化学行为)、化疗所致的周围神经病变 (CIPN)和步态变化是铂类药物(如顺铂)治疗癌症的衰弱副作用， 紫杉烷和长春花碱。顺铂被广泛用作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治疗后经历了CRCI、CIPN和/或跌倒，损害 他们的生活质量。这些神经毒性损伤也会影响顺铂的治疗，影响 疾病的发展。目前，还没有FDA批准的临床干预措施来治疗CRCI和 CIPN。从机制上讲，顺铂诱导的神经元毒性源于核和线粒体DNA损伤， 和氧化应激，诱导丝裂原活化蛋白激酶(MAPK)p38MAPK的激活 和c-jun氨基末端激酶(JNK)，导致神经元凋亡。我们的初步数据显示，在体外 小分子抑制剂对p38MAPK的药理抑制作用和SP600125对p38MAPK和SP600125的抑制作用 JNK，防止顺铂引起的树突棘分支和密度的减少。根据这些数据，我们 假设抑制p38MAPK/JNK通路将阻止顺铂诱导的神经元 细胞凋亡和损伤，导致认知障碍、步态改变和神经病变的减轻 与CRCI和CIPN相关的疼痛。在这个项目中，我们建议确定：(1)顺铂诱导的p38 MAPK/JNK信号通路在结构和功能神经元损伤中的作用 抑制和siRNA沉默；(2)奈法帕莫特和SP600125预防顺铂所致的神经病变和步态 C57BL/6小鼠ID8同基因上皮性卵巢癌和转基因乳腺癌的变化 (3)p38MAPK/JNK抑制顺铂的神经毒性作用 而不影响其抗癌活性。我们的方法包括两个独立的神经细胞的体外分析。 LINES，使用CIPN感觉测试的行为分析，认知障碍测试，以及新颖 MouseWalker使用两种小鼠癌症模型研究雌性小鼠步态变化。拟议的研究将 证明p38MAPK和JNK在顺铂诱导的CRCI/CIPN中的作用，以及 治疗CRCI和CIPN的新策略。由于健康差距，女性更不成比例地患有 癌症和疼痛相关的治疗要比男性多。因此，在雌性小鼠身上测试我们的假设有望 显著提高对顺铂所致神经毒性副作用的认识和治疗水平 癌症女性的生活质量。然而，我们预计这些发现也可能适用于顺铂- 对男性以及对卵巢癌和乳腺癌以外的其他癌症的神经毒性。

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.