Neurotrophic strategy to mitigate chemotherapy-related brain injury

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ABSTRACT Cancer-related cognitive impairment (CRCI), often referred as “chemobrain”, is prevalent up to 75% of all breast cancer survivors. These impairments cause significant distress and reduce the quality for life for survivors. Despite growing realization of the long-term clinical problem of CRCI in millions of cancer survivors, there is a conspicuous absence of clinical recourse available. Therefore, regenerative strategies to restore cognition and normal brain function in the cancer patients and survivors are clearly needed. Our past clinical and pre-clinical studies have established that doxorubicin, which is commonly used in breast cancer, can lead to a significant decline in the blood (human) and brain (rodent) levels of brain derived neurotrophic factor (BDNF). BDNF is abundantly expressed in the prefrontal cortex and hippocampus and plays important roles in neuronal repair and survival, dendritic and axonal growth, long-term potentiation, and neural stem cell maintenance. In our human studies, pathological reductions of BDNF were linked to higher risk of cognitive toxicity. Similarly, we have shown that chronic chemotherapy significantly impaired performance on the hippocampus and cortex-dependent cognitive tasks in the rodents. These deficits were linked with reduced neurogenesis, elevated neuroinflammation, and significant damage to the newly born and mature neuronal architecture, dendrites, spines, and synaptic integrity. To mitigate these deficits, our preliminary rodent studies involving mice receiving doxorubicin with riluzole, an orally active glutamate-modulating medication, has prevented the reduction of hippocampus BDNF levels. Thus, we hypothesize that: i) chemotherapy-induced reduction of BDNF leads to the long-term neurodegenerative consequences culminating into cognitive impairments and, ii) augmentation of BDNF in vivo will restore cognitive function in brains exposed to chemotherapy and will provide neuroprotection against CRCI. We will test our hypothesis with three specific aims. In Aim 1, we will systematically examine brain and plasma BDNF levels to link its trajectory with CRCI and neurobiological underpinnings in a mouse model of breast cancer chemotherapy. In Aim 2, we will determine the neuroprotective impact of enhancing BDNF in vivo to reverse CRCI. In Aim 3, we will evaluate the neuroprotective effect of BDNF-enhancing riluzole to ameliorate CRCI. This study will link the neurobiological underpinnings of chemotherapy and neuroprotective effects of BDNF against CRCI. If demonstrated to be successful, our translationally feasible pharmacological approach will provide basis for future studies to repurpose riluzole as a therapeutic option for mitigating CRCI.