Mechanisms underlying radiation-and chemotherapy induced cognitive impairment.

 描述（由申请方提供）：原发性和继发性脑恶性肿瘤常规接受放疗联合同步和辅助化疗，一线治疗仍然是抑制疾病进展的唯一可行选择。不幸的是，这些治疗导致了认知功能的衰弱，越来越多的患者在严重的神经认知后遗症中存活时间更长。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疗和化疗引起的认知障碍的机制基础。小鼠将接受设计为近似临床治疗方案的辐照和化疗范例，重点是通常用于治疗脑癌的分次辐照和替莫唑胺（TMZ）的组合方案。在治疗后早期（2个月）和后期（6个月）进行的严格行为评估将与分子，细胞和电生理学研究相结合，旨在测试我们的总体假设，即神经元解剖结构和CB 1信号传导的破坏是当前癌症治疗方案引起的许多非预期认知下降的贡献，如果不是因果关系的话。我们已经量化了一系列的神经元形态学参数在不同剂量和时间后照射和/或化疗，并发现显着和持久的减少树突的复杂性和棘，是时间上一致的突触完整性的变化。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可塑性和认知功能。我们最近还发现，辐射导致与认知功能障碍相关的大麻素受体（1型，CB 1）的快速和持续上调。电生理学测量已经证实，照射显着改变CB 1介导的神经传递，从而扰乱受照射的大脑的抑制/兴奋性的基调。CB 1受体是神经递质释放的主要突触前调节剂，我们的数据表明，细胞毒性癌症治疗会破坏大脑中的大麻素信号传导，对认知产生显著的不良影响。重要的是，我们现在已经发现了新的数据，表明CB 1受体的无毒血脑屏障渗透拮抗剂（反向激动剂），即AM 251，可以预防辐射诱导的认知障碍时，照射后给药。我们将探讨这种针对大麻素信号传导轴的新策略是否为减少脑细胞毒性癌症治疗的不良影响提供了潜在的治疗干预。治疗后将研究海马和内侧前额叶皮质中特定神经元群体敏感性的区域差异，以进一步阐明使受损CNS中突触强度、连接性和功能不稳定的急性和慢性机制。

 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.