Treatment of the Chronic Blast-induced PTSD Phenotype with Capsaicin

摘要 在伊拉克和阿富汗战场上发生的爆炸相关创伤性脑损伤(TBI)与 随着神经精神损伤的发展(包括创伤后应激障碍[PTSD]和 忧郁症)。爆炸相关脑外伤的治疗目前仅限于咨询和姑息治疗。 我们在大鼠模型中探索了模拟轻度脑损伤(MTBI)的74.5 kpa冲击波暴露的影响。爆炸- 暴露于创伤后应激障碍的大鼠表现出各种类似创伤后应激障碍的行为特征，包括焦虑增加，听觉增强 惊吓，改变对捕食者气味的反应，以及改变暗示的恐惧反应。进一步的实验证据 表明脑血管系统是冲击波的主要目标，如急性和慢性血管 在冲击波暴露后，会发生退化过程。在随后的研究中，我们发现mGluR2/3 受体拮抗剂(BCI-838)能够逆转大多数大鼠的创伤后应激障碍相关特征。这导致了 观察到大鼠冲击伤后mGluR2/3表达增加。随后的研究表明， 这种mGluR2/3表达的增加导致其调控靶点TRPV1的表达下降。 辣椒素是一种生物碱，已知能激活TRPV1，并具有抗抑郁和缓解焦虑的特性。 此外，它还具有很强的血管生成保护作用。拟议研究的总体目标是测试 全身应用辣椒素能否逆转已建立的脑血管和认知功能退行性变 在我们的冲击波诱导的mTBI大鼠模型中存在的过程。我们建议给爆炸暴露的大鼠注射辣椒素 (3×74.5 kpa)一旦他们发展出慢性创伤后应激障碍表型(爆炸后6个月)进行测试 这种治疗是否改善了与疾病相关的认知障碍和血管改变。我们会 抑郁测试(强迫游泳和新奇抑制摄食测试)，记忆测试(莫里斯水迷宫)， 背景和线索恐惧条件作用，以及新奇的物体识别。使用微型X射线计算机断层扫描技术， 免疫组织化学和体视学方法，我们将分析脑血管系统的变化，包括 存在异常的血管系统以及血管密度、长度、表面和体积的变化。生化 分析将确定在辣椒素治疗过程中血管系统中发生的任何分子结构变化。 总的来说，拟议的研究将探索辣椒素及其制剂的潜在治疗益处。 靶向TRPV1治疗原始性创伤后应激障碍这些研究可能会发现新的治疗方案。 用于治疗受这一毁灭性疾病影响的现役军人和退伍军人。

Summary Blast-related traumatic brain injury (TBI) incurred in the war theaters of Iraq and Afghanistan is associated with the development of neuropsychiatric injuries (including post-traumatic stress disorder [PTSD] and major depression) among soldiers. Treatment for blast-related TBI is currently limited to counseling and palliative care. We have explored the effects of 74.5-kPa blast exposures that mimic mild TBI (mTBI) in a rat model. Blast- exposed rats exhibit a variety of PTSD-like behavioral traits, including increased anxiety, enhanced acoustic startle, altered responses to a predator scent, and altered cued fear responses. Further experimental evidence indicates that the cerebral vasculature is a main target for blast waves, as acute and chronic vascular degenerative processes develop after blast exposures. In subsequent studies, we found that a mGluR2/3 receptor antagonist (BCI-838) is able to reverse most of the PTSD-related traits seen in rats. This led to the observation that mGluR2/3 expression is increased following blast injury in the rat. Subsequent studies showed that this increased mGluR2/3 expression results in decreased expression of TRPV1, its modulating target. Capsaicin is an alkaloid known to activate TRPV1 and to have antidepressant and anxiolytic properties. In addition, it has strong angiogenic protective properties. The overall goal of the proposed research is to test whether systemic administration of capsaicin can reverse the established cerebrovascular and cognitive degenerative processes present in our rat model of blast-induced mTBI. We propose to administer capsaicin to blast-exposed rats (3 × 74.5 kPa) once they have developed the chronic PTSD phenotype (6 months post-blast exposure) to test whether this treatment improves the cognitive deficits and vascular alterations associated with the condition. We will test for depression (forced swimming and novelty-suppressed feeding tests), memory (Morris Water Maze), contextual and cued fear conditioning, and novel object recognition. Using micro X-ray computed tomography, immunohistochemical, and stereological methods, we will analyze alterations in the brain vasculature, including the presence of abnormal vasculature and changes in vascular density, length, surface, and volume. Biochemical analyses will identify any molecular structural changes in the vasculature that occur with capsaicin treatment. Collectively, the proposed studies will explore the potential therapeutic benefits of capsaicin and agents targeting TRPV1 for the treatment of blast-induced PTSD. These studies may uncover new therapeutic options for the treatment of active duty military personnel and veterans affected by this devastating condition.