Neurotrophic strategy to mitigate chemotherapy-related brain injury

摘要 癌症相关的认知障碍（CRCI），通常被称为“化学因子”， 75%的乳腺癌幸存者。这些损伤会造成严重的痛苦，并减少 生存者的生活质量。尽管人们越来越认识到CRCI的长期临床问题， 在数百万癌症幸存者中，明显缺乏临床求助手段。 因此，再生策略，以恢复认知和正常的脑功能，在癌症 病人和幸存者显然是需要的。我们过去的临床和临床前研究 多柔比星是乳腺癌的常用药物， 脑源性神经营养因子（BDNF）的血液（人）和脑（啮齿动物）水平下降。 脑源性神经营养因子在前额叶皮层和海马中大量表达， 在神经元修复和存活、树突和轴突生长、长时程增强中的作用， 神经干细胞移植在我们的人类研究中，BDNF的病理性减少与 认知毒性风险更高。同样，我们已经证明， 海马和皮层依赖的认知任务的表现显着受损， 啮齿动物这些缺陷与神经发生减少，神经炎症增加， 以及对新生和成熟的神经元结构、树突、棘 和突触完整性为了减轻这些缺陷，我们的初步啮齿动物研究涉及小鼠， 接受多柔比星与利鲁唑（一种口服谷氨酸调节药物）， 防止海马BDNF水平的降低。因此，我们假设：i） 化疗诱导的BDNF减少导致长期的神经退行性变 最终导致认知障碍的后果，以及，ii）体内BDNF的增加将 恢复暴露于化疗的大脑的认知功能，并提供神经保护 反对CRCI。我们将用三个具体目标来检验我们的假设。在目标1中，我们将系统地 检查脑和血浆BDNF水平，将其轨迹与CRCI和神经生物学联系起来， 乳腺癌化疗小鼠模型的基础。在目标2中，我们将确定 增强BDNF在体内逆转CRCI的神经保护作用。在目标3中，我们将评估 增强BDNF的利鲁唑对改善CRCI的神经保护作用。这项研究将把 化疗的神经生物学基础和BDNF的神经保护作用， CRCI。如果证明是成功的，我们的预防可行的药理学 这种方法将为将来的研究提供基础，重新将利鲁唑作为一种治疗选择 缓解CRCI。

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.