Mechanisms underlying radiation-and chemotherapy induced cognitive impairment.

 描述(申请人提供)：大脑的原发和继发性恶性肿瘤通常接受放射治疗，同时进行辅助化疗，这些一线治疗仍然是抑制疾病进展的唯一可行的选择。不幸的是，这些治疗会产生令人衰弱的认知副作用，越来越多的患者患有严重的神经认知后遗症，存活时间更长。治疗引起的认知功能障碍的负面影响越来越被认为是评估治疗结果和确定长期治疗质量的关键标准。 生活。因此，我们提出了一系列新的研究来阐明放化疗导致认知障碍的机制基础。小鼠将接受旨在接近临床治疗方案的放射和化疗方案，重点是分次放射和替莫唑胺(TMZ)的联合方案，该方案通常用于治疗脑癌。在治疗早期(2个月)和后期(6个月)进行严格的行为评估，将结合分子、细胞和电生理学研究，旨在测试我们的总体假设，即神经元解剖和CB1信号的中断即使不是当前癌症治疗方案导致的许多意外认知能力下降的原因，也是促成的。我们量化了放射和/或化疗后不同剂量和不同时间的一系列神经元形态计量参数，发现树突复杂性和棘突的显著和持续减少与突触完整性的变化在时间上是一致的。我们推测，这些神经元和突触形态的超微结构变化将损害突触的可塑性和认知功能。我们最近还发现，辐射导致大麻素受体(1型，CB1)的快速和持续上调，这与认知功能障碍有关。电生理测量已经证实，辐射显着改变CB1介导的神经传递，从而扰乱受辐射大脑的抑制/兴奋音调。CB1受体是神经递质释放的主要突触前调节器，我们的数据表明，细胞毒性癌症治疗扰乱了大脑中的大麻素信号，对认知有显著的不良影响。重要的是，我们现在发现了新的数据，表明一种无毒的血脑屏障CB1受体的永久拮抗剂(反向激动剂)，即AM251，在辐射后给药时可以预防辐射引起的认知障碍。我们将探索这一针对大麻素信号轴的新策略是否为减少脑部细胞毒性癌症治疗的不良影响提供了一种潜在的治疗干预措施。治疗后将研究海马区和内侧前额叶皮质特定神经元群体敏感性的区域差异，以进一步阐明破坏受损中枢神经系统突触强度、连接性和功能的急性和慢性机制。

 DESCRIPTION (provided by applicant): Primary and secondary malignancies of the brain are routinely subject to radiotherapy in combination with concurrent and adjuvant chemotherapy, frontline treatments that remain the only tenable option for providing a restraint on disease progression. Unfortunately, debilitating cognitive side effects result from these treatments, and growing numbers of patients are surviving longer with severe neurocognitive sequelae. The negative impact of treatment-induced cognitive dysfunction is becoming increasingly recognized as a critical criterion for evaluating therapeutic outcome and for determining long-term quality of life. Thus, we propose a series of novel studies to elucidate the mechanistic basis of radiation and chemotherapy-induced cognitive impairment. Mice will be subjected to irradiation and chemotherapy paradigms designed to approximate clinical treatment scenarios, with a focus on a combined regimen of fractionated irradiation and temozolomide (TMZ) that is commonly used for the treatment of brain cancer. Rigorous behavioral assessments conducted at early (2 month) and latter times (6 months) post-treatment, will be coupled with molecular, cellular and electrophysiologic studies designed to test our overarching hypothesis that disruptions to neuronal anatomy and CB1 signaling are contributory if not causal to many of the unintended cognitive decrements caused by current cancer treatment regimes. We have quantified a range of neuronal morphometric parameters at different doses and times after irradiation and/or chemotherapy and found both marked and persistent reductions in dendritic complexity and spines that are temporally coincident with changes in synaptic integrity. We hypothesize that these ultrastructural changes in neuronal and synaptic morphology will compromise synaptic plasticity and cognitive function. We have also recently found that irradiation leads to a rapid and persistent upregulation of cannabinoid receptors (type 1, CB1) that is associated with cognitive dysfunction. Electrophysiologic measurements have confirmed that irradiation significantly alters CB1 mediated neurotransmission thereby perturbing the inhibitory/excitatory tone of the irradiated brain. The CB1 receptor is a major pre-synaptic modulator of neurotransmitter release, and our data suggest that cytotoxic cancer treatments disrupt cannabinoid signaling in the brain with significant adverse effects on cognition. Importantly, we have now uncovered new data demonstrating that a non-toxic, blood brain barrier permeant antagonist (inverse agonist) of CB1 receptors, namely AM251, can prevent radiation-induced cognitive impairment when administered after irradiation. We will explore whether this novel strategy targeted to the cannabinoid-signaling axis, provides a potential therapeutic intervention for reducing the adverse effects of cytotoxic cancer treatments in the brain. Regional differences in the sensitivity of specific neuronal populations in the hippocampus and medial prefrontal cortex will be investigated after treatment to elucidate further the acute and chronic mechanisms that destabilize synaptic strength, connectivity and functionality in the injured CNS.