UC Irvine

Abstract

OBJECTIVES

Chemotherapy-related cognitive impairment (CRCI) is an adverse sequela of cancer treatment commonly reported in cancer survivors. Cisplatin is used for the treatment of various malignancies including ovarian, testicular, head and neck cancers, and pediatric brain tumors. More than 30% of advanced ovarian cancer patients develop CRCI during and after platinum-based chemotherapy. We examined the role of p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) activation in cisplatin-induced CRCI, and whether the small molecule p38 MAPK inhibitor Neflamapimod and JNK inhibitor SP600125, can prevent cisplatin-induced neuronal damage. The p38 and JNK MAPK signaling pathways are involved in various stress response pathways in the CNS including oxidative stress.

METHODS

The effect of cisplatin on cognition in an ovarian cancer female rat model was assessed by novel object recognition (NOR). Hippocampal glutathione levels were measured post-behavioral testing. P38 and JNK MAPK signaling activation were assessed in the neural cell lines PC12 and SH-SY5Y by Western blot. Cultured hippocampal neurons were pretreated with Neflamapimod or SP600125 followed by cisplatin for 24 hours, and dendritic spine density and branch length were quantified.

RESULTS

Cisplatin increased phospho-p38 and phospho-JNK MAPK protein levels in PC12 and SH-SY5Y cells. Cisplatin reduced dendritic branching and spine density, which was prevented by Neflamapimod and SP600125 pre-treatment in hippocampal neurons, in vitro. Chronic cisplatin treatment decreased hippocampal glutathione levels and impaired cognitive function in the ovarian cancer rat model.

DISCUSSION

The cognitive deficits caused by cisplatin results in part from dendritic damage and neural apoptosis, which is mediated by oxidative stress and the p38 and JNK MAPK pathways. P38 and JNK MAPK inhibition mitigated cisplatin-induced dendritic spine loss and branching in vitro. Next, we will examine whether Neflamapimod and SP600125 administration in an ovarian cancer rat model is safe and if they can prevent cognitive impairment.