UC Irvine

Abstract

OBJECTIVES

Chemotherapy-related cognitive impairment (CRCI) and chemotherapy-induced peripheral neuropathy (CIPN) are neurological complications of cancer treatment. Cisplatin is used to treat ovarian malignancies, and over 70% of women experience CRCI/CIPN during and after platinum-based chemoTx. However, over 30% of non-CNS cancer patients experience cognitive impairment prior to chemoTx. To examine the contribution of cancer itself and additional neurological impairment with chemoTx, we used an ID8 syngeneic mouse model of ovarian cancer and assessed hyperalgesia and cognition +/- cisplatin treatment.

METHODS

C57BL/6 female mice were injected intraperitoneally with 107 ID8 ovarian cancer cells or 0.9% saline. After 10d of ID8 injections, mice received cisplatin (2.3 mg/kg/day, i.p.) or 0.9% saline (OvT+CIS, OvT+VEH, respectively) for 5d, followed by 5d of rest for 2 cycles. Mechanical and cold hyperalgesia were assessed longitudinally. Cognition was assessed 28d post-chemoTx by the open field test (OFT), novel object recognition (NOR), and novel place recognition (NPR) tasks.

RESULTS

OvT+VEH and OvT+CIS mice developed an increased sensitivity to mechanical ( >200%, p< 0.001) and thermal (cold) stimuli ( >78%, p< 0.004) starting 14d post-ID8 implantation, vs non-tumor controls (CON). In the OFT, OvT+CIS mice had increased anxiogenic behavior (55%, p< 0.001) vs CON, and (46%, p< 0.05) vs OvT+VEH. In NPR, OvT+CIS had reduced discrimination (37%, p< 0.05) vs CON. OvT+VEH and OvT+CIS showed impaired discrimination (25%, p< 0.05 & 33%, p< 0.01, respectively) in NOR vs CON, with trending differences between OvT+CIS vs OvT+VEH in hyperalgesia and cognitive tasks. DISCUSSION: This is the first rodent model to demonstrate that ovarian cancer may evoke sensory and neurocognitive changes in the absence of chemotherapy. Future development of the model will address hyperalgesia and cognitive differences between OvT+VEH vs OvT+CIS. This model has potential for translational studies on the treatment of neurological sequelae of cancer and cisplatin-induced CRCI and CIPN.