Nanoparticles Mitigate Chronic Behavior and Neuropathology

越来越多的美国退伍军人从遭受爆炸袭击的军事企业返回， 创伤性脑损伤（TBI）。迫切需要更好地理解长期和削弱 认知、心理健康和感觉运动能力的损伤。使伤口更加复杂， 反复遭受碎屑脑震荡的战斗人员可能会出现长期后遗症。的 随着当前战争的进行，这些人的数量正在增加，这对国防部构成了重大挑战 退伍军人事务部来自运动员、平民和军人群体的证据表明， 与脑震荡史相关的心理和神经认知结果。研究五味子甲 重复爆炸暴露如何影响后续冲击相关TBI后的恢复， 将使用结合多种爆炸引起的神经创伤和流体冲击（FPI）的模型。此外，本发明还 迫切需要在TBI恢复的多个阶段进行治疗。这项研究还将测试一种新药 可以减少重复冲击波后观察到的持续性行为和神经病理学影响的治疗 暴露，然后是FPI诱导的TBI。我们设计了一种治疗方法，可以阻止神经退行性变， 在创伤后使用止血纳米颗粒（hNPs）已被证明可以减少出血和增加 在包括爆炸在内的多重创伤模型中存活。我们的数据表明，hNPs减轻焦虑样行为 爆炸后。使用hNP比传统的药物递送具有优势，因为我们可以设计版本， 有助于改善药物在大脑中的传递和生物利用度。我们假设载药的hNPs将使 表现出与持续性认知和认知障碍相当的症状的动物的恢复更成功， TBI退伍军人的神经精神症状。我们的假设是基于hNP改善了 血脑屏障完整性，减少氧化应激和减少与冲击波TBI相关的神经炎症， 这会导致大脑功能的长期变化，并产生负面的行为结果。扩大 在本研究的范围内，我们还将在随后的FPI诱导的TBI后立即测试这些颗粒。 我们的目标是开发一种易于交付的临床转化药物治疗方法， 同时减轻神经病理学并促进TBI后恢复。为了实现这一目标，我们建议使用 退伍军人相关的啮齿动物模型，以（1）确定延迟全身施用的tempol 重复冲击伤后hNP或对照，（2）表征退伍军人相关的基线损伤水平， 由重复冲击波暴露和延迟FPI诱导的TBI组成的复杂TBI模型（3）确定了 在FPI诱导的TBI（重复冲击后）后Tempol hNP或对照的急性递送的功效 暴露）以减轻氧化应激和神经胶质增生，以及（4）测定tempol hNP急性递送的能力 或FPI诱导的TBI（重复冲击后）后的对照，以减少慢性行为和 神经病理学结果。这项研究将调查hNPs的承诺，无论是延迟治疗， 反复冲击波TBI和随后FPI诱导的TBI的急性治疗。

Increasing numbers of US Veterans are returning from military ventures suffering from blast exposure and traumatic brain injury (TBI). There is a critical need for a greater understanding of the long term and debilitating impairments in cognition, psychological health, and sensorimotor abilities. To further complicate the injury, combat personnel exposed to repeated clast concussions could find themselves with long-term sequelae. The number of these individuals is increasing with the current war and poses a major challenge for the Department of Veterans Affairs. Evidence from athlete, civilian, and military populations suggests a possible `injury frequency effect' associated with concussion history for psychological and neurocognitive outcomes. To study the effects of how repeated blast exposure influences recovery after a subsequent impact-related TBI, established animal models combining multiple blast-induced neurotraumas and fluid percussion impact (FPI) will be used. Further, there is a dire need for treatment at multiple stages of TBI recovery. This research will also test a novel drug therapy that can reduce the persistent behavioral and neuropathological effects observed after repeated blast exposures followed by FPI-induced TBI. We have engineered a therapy that can halt neurodegeneration when administered after trauma. Hemostatic nanoparticles (hNPs) have been shown to reduce bleeding and increase survival in multiple trauma models, including blast. Our data indicates that hNPs alleviate anxiety-like behaviors following blast. The use of hNPs have advantages over traditional drug delivery as we can engineer versions to help improve drug delivery and bioavailability in the brain. We hypothesize that drug-loaded hNPs will enable more successful recovery of animals exhibiting symptoms comparable to the persistent cognitive and neuropsychiatric symptoms of TBI Veterans. We base our hypothesis on the premise that hNPs improve the blood brain barrier integrity, diminish oxidative stress and reduce neuroinflammation associated with blast TBI, which can induce long-lasting changes in brain function and produce negative behavioral outcomes. Expanding the scope of this study, we will also test these particles immediately after a subsequent FPI-induced TBI. Our objective is to develop an easily delivered, clinically translational pharmacotherapeuthic approach to simultaneously mitigate neuropathology and promote post-TBI recovery. To achieve this, we proposed to use Veteran-relevant rodent models to (1) determine the effect of delaying the systemically administered tempol hNPs or controls following repeated blast injury, (2) characterize the baseline injury levels of a Veteran-relevant complex TBI model that consists of repetitive blast exposure and delayed FPI-induced TBI (3) determine the efficacy of acute delivery of tempol hNPs or controls following FPI-induced TBI (subsequent to repeated blast exposure) to mitigate oxidative stress and gliosis and (4) determine the ability of acute delivery of tempol hNPs or controls following FPI-induced TBI (subsequent to repeated blast) to reduce chronic behavioral and neuropathological outcomes. This study will investigate the promise of hNPs for both a delayed treatment for repeated blast TBIs and an acute treatment for a subsequent FPI-induced TBI.