Nanoparticles Mitigate Chronic Behavior and Neuropathology

越来越多的美国退伍军人从军事冒险中返回，遭受爆炸暴露和 创伤性脑损伤(TBI)。迫切需要更好地理解长期和衰弱的 认知、心理健康和感觉运动能力受损。让伤势更加复杂的是， 暴露在反复碎裂脑震荡中的战斗人员可能会发现自己有长期的后遗症。这个 随着当前的战争，这些人的数量正在增加，这对该部构成了重大挑战 退伍军人事务部。来自运动员、平民和军人人群的证据表明，可能存在受伤的频率 脑震荡病史对心理和神经认知结果的影响。要研究这些影响 反复冲击波暴露如何影响随后与撞击相关的脑损伤后的康复，建立动物 将使用多个冲击波诱导的神经创伤和流体冲击冲击(FPI)相结合的模型。此外， 在创伤性脑损伤恢复的多个阶段迫切需要治疗。这项研究还将测试一种新药 可减少反复爆炸后观察到的持续性行为和神经病理影响的治疗 暴露之后是FPI诱导的脑损伤。我们已经设计出一种疗法，可以在以下情况下阻止神经退化 在创伤后给药。止血纳米粒(HNPs)已被证明可以减少出血和增加出血 在多种创伤模型中存活，包括BLAST。我们的数据表明，hNPs可以缓解类似焦虑的行为 在爆炸之后。使用hNPs比传统的药物输送有优势，因为我们可以设计出不同的版本来 帮助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 更成功地恢复了动物的症状，表现出与持续性认知和 颅脑损伤退伍军人的神经精神症状我们的假设基于这样一个前提，即hNPs可以改善 血脑屏障完整性，减少氧化应激，减少与冲击性脑损伤相关的神经炎症， 这可能会导致大脑功能的长期变化，并产生负面的行为结果。正在扩张 在这项研究的范围内，我们还将在随后的FPI诱导的脑损伤后立即测试这些颗粒。 我们的目标是开发一种易于交付的、临床翻译的药物疗法方法 同时减轻神经病理，促进脑损伤后恢复。为了实现这一点，我们建议使用 退伍军人相关啮齿动物模型(1)确定延迟全身给药的效果 反复冲击伤后的hNPs或对照，(2)表征与退伍军人相关的基线损伤水平 由重复冲击波暴露和延迟的FPI诱导的复杂的TBI模型(3)决定了 FPI诱导的颅脑损伤后(重复冲击波后)急性注射tempolhNPs或对照组的疗效 暴露)以减轻氧化应激和胶质增生，以及(4)确定tempolhNPs的急性递送能力 或对照组在FPI诱导的TBI(重复冲击后)减少慢性行为和 神经病理结果。这项研究将调查hNPs对延迟治疗两种疾病的前景 反复冲击性颅脑损伤和对随后的急性颅脑损伤的急性治疗。

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.