Advances in cancer treatment, chemotherapy in particular, have substantially increased the number of long-term cancer survivors. However, these drugs often have neurotoxic effects that impair cognitive function, thereby diminishing the quality of life of millions of cancer survivors. Chemotherapy-related cognitive impairment (CRCI, chemo-brain) is commonly reported following the administration of chemotherapeutic agents and comprises a wide variety of neurological problems. Cisplatin is used to treat breast cancer and advanced ovarian cancer among other malignancies. Notably, more than 30% of advanced ovarian cancer patients develop CRCI during and after cisplatin-based chemotherapy. A plausible explanation for CRCI is that cisplatin might impair the structure and functions of neurons in brain regions involved in learning and memory, such as the hippocampus. We have recently identified mitochondrial dysfunction and increased oxidative stress as a mechanism through which cisplatin causes hippocampal cell death, and severe dendritic damage in surviving neurons. The aims of this study were to examine the effect of the antioxidant N-acetylcysteine (NAC) in mitigating cisplatin-induced hippocampal damage and assesse the effect of cisplatin on cognitive performance in a rat model.
At a high dose, cisplatin (1μM) induced ∼35% increase in caspase-9 activation in primary rat hippocampal neurons, whereas at a substantially lower dose, cisplatin (0.1μM) induced non-reversible damage to dendritic spines and branches. Both doses produced severe mitochondrial respiratory deficits and significant ROS production. Delayed treatment with NAC partially mitigated neuronal apoptosis and ameliorated cisplatin induced dendritic spine loss. When administered to adult Sprague Dawley rats, cisplatin (3 mg/kg) administered for two consecutive days caused ∼40% reduction in the number of dendritic spines in CA1 and CA3 hippocampal neurons.
Lastly, cognitive testing of rats treated with a chronic cisplatin regimen, revealed significant deficits in hippocampus-dependent tasks. Rats were given weekly cisplatin (5mg/kg, i.p.) or saline injections for 4 weeks and then trained in Context-Object Discrimination, 6 weeks later (n = 7,8). Cisplatin-treated rats were impaired in discriminating between the out-of-context and in-context object.
Mitochondrial dysfunction provokes free radical production, with resulting loss of dendritic spines. When administered to rats, cisplatin causes hippocampal neuronal and mitochondrial damage, as well as cognitive deficits, supporting that role of mitochondrial toxicity in the mechanisms of cisplatin-induced CRCI. Importantly the data demonstrates that these processes can be potentially mitigated with administration of the clinically available antioxidant, NAC. The effect of NAC in ameliorating cisplatin induced CRCI in rats is being evaluated.
Citation Format: Naomi Lomeli, Jennifer Czerniawski, Kaijun Di, John Guzowski, Daniela Bota. Cisplatin induces mitochondrial damage and hippocampal neurotoxicity: a potential mechanism for chemotherapy-related cognitive impairment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4782.
- ©2016 American Association for Cancer Research.