Neurotrophic strategy to mitigate chemotherapy-related brain injury

减轻化疗相关脑损伤的神经营养策略

基本信息

批准号：
10735146
负责人：
Munjal M Acharya
金额：
$ 47.1万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-06 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735146
关键词：
Amygdaloid structure Architecture Blood Brain Brain Injuries Brain-Derived Neurotrophic Factor Breast Cancer Model Breast Cancer Treatment Breast Cancer survivor Cancer Patient Cancer Survivor Cell Culture Techniques Cell Maintenance Chemotherapy-Oncologic Procedure Chronic Clinical Clinical Data Clinical Research Cognition Cognitive Cognitive deficits Cyclophosphamide Data Dendrites Disease Distress Doxorubicin Drug Kinetics Electrophysiology (science)Ensure Exposure to Future Genetic Glutamates Hippocampus Human Impaired cognition Impairment Link Long-Term Potentiation Measurement Mediating Modeling Mus Nerve Degeneration Neurobiology Neurons Oral Pathologic Patients Performance Pharmaceutical Preparations Plasma Play Pre-Clinical Model Prefrontal Cortex Quality of life Riluzole Risk Rodent Rodent Model Role Safety Series Severities Slice Survivors Synapses Testing Therapeutic Toxic effect Vertebral column axon growth behavior measurement cancer therapy cancer-related cognitive impairment chemobrain chemotherapy cognitive function cognitive task enhancing factor high risk improved in vivo malignant breast neoplasm mouse model nerve stem cell neural circuit neurogenesis neuroinflammation neuroprotection pharmacologic phase 1 study pre-clinical preclinical study prevent regenerative approach repaired response side effect stem cell proliferation

项目摘要

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.

抽象的癌症相关认知障碍（CRCI），通常被称为“化学脑”，在 75% 的乳腺癌幸存者会因这些损伤而感到严重痛苦并降低生存率。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，明显缺乏可用的临床资源。因此，恢复癌症患者的认知和正常脑功能的再生策略我们过去的临床和临床前研究显然需要患者和幸存者。已证实常用于乳腺癌治疗的多柔比星可导致显着的血液（人类）和大脑（啮齿动物）脑源性神经营养因子（BDNF）水平下降。 BDNF 在前额皮质和海马体中大量表达，发挥着重要作用在神经元修复和存活、树突和轴突生长、长时程增强和在我们的人类研究中，BDNF 的病理性减少是相关的。同样，我们已经证明，慢性化疗会导致更高的认知毒性风险。海马体和皮质依赖性认知任务的表现显着受损这些缺陷与神经发生减少、神经炎症增加有关，对新生和成熟的神经结构、树突、脊柱造成严重损害，为了减轻这些缺陷，我们对小鼠进行了初步的啮齿动物研究。接受阿霉素和利鲁唑（一种口服活性谷氨酸调节药物），阻止海马 BDNF 水平的降低因此，我们发现：i) 化疗引起的 BDNF 减少导致长期神经退行性病变最终导致认知障碍的后果，ii) 体内 BDNF 的增强将恢复接受化疗的大脑的认知功能，并提供神经保护针对 CRCI，我们将通过三个具体目标来系统地检验我们的假设。检查大脑和血浆 BDNF 水平，将其轨迹与 CRCI 和神经生物学联系起来在目标 2 中，我们将确定乳腺癌化疗小鼠模型的基础。在目标 3 中，我们将评估体内增强 BDNF 对逆转 CRCI 的神经保护作用。增强 BDNF 的利鲁唑对改善 CRCI 的神经保护作用。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，我们的药理学具有转化可行性。该方法将为未来研究重新利用利鲁唑作为治疗选择提供基础用于减轻 CRCI。