UC Irvine

Abstract OBJECTIVES: Chemotherapy-related cognitive impairment (CRCI) is widely reported among cancer survivors. We focus on the neurocognitive impairments provoked by cisplatin, which is used for 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 cisplatin-based chemotherapy. We examined the role of brain-derived neurotrophic factor (BDNF) downregulation in cisplatin-induced CRCI, and whether pharmacological BDNF augmentation via ampakines can prevent cisplatin-induced neuronal damage. BDNF is broadly expressed in the hippocampus where it regulates dendritic spine integrity and neurogenesis, among other functions.

METHODS

We examined the effects of cisplatin on neurogenesis, neuronal morphology, BDNF levels, and cognition in rats. We also assessed the effects of cisplatin on dendritic spine density, BDNF mRNA levels, apoptosis, and the ability of ampakine CX1739 to mitigate cisplatin-induced neuronal damage in-vitro.

RESULTS

Cisplatin reduced dendritic branching and spine density, and neurogenesis in the rat hippocampus. Chronic cisplatin treatment decreased hippocampal and serum BDNF levels, and impaired cognitive function in rats. In-vitro, ampakine administration upregulated BDNF levels, and mitigated cisplatin-induced dendritic damage in cultured hippocampal neurons. Concomitant administration of CX1739 with cisplatin did not affect cisplatins cytotoxic activity in two ovarian cancer cell lines. DISCUSSION: The cognitive deficits caused by cisplatin in rats result from the loss of excitatory synapses and dendritic spines that anchor them, neuronal apoptosis, as well as decrease in neurogenesis. Changes in BDNF levels are associated with cisplatin-induced CRCI. Importantly, CX1739 mitigated cisplatin-induced neurotoxicity and BDNF depletion in vitro. Next, we will examine whether CX1739 prevents cisplatin-induced cognitive deficits in rats. If so, we will plan a Phase I study to examine if ampakine administration to ovarian cancer patients receiving cisplatin is safe, and if it ameliorates the cognitive deficits described in this patient population.