Pathology-directed combination therapy for pediatric TBI

描述（由申请人提供）：创伤性脑损伤（TBI）是婴儿和4岁以下儿童发病率和死亡率的主要原因之一。与年龄较大的儿童和成人的情况一样，损伤严重程度的范围从轻度到重度，其中轻度至中度损伤患者是主要人群。此外，支持性神经重症监护的有效性增加，显著降低了死亡率。总的来说，这些现象导致越来越多的TBI幸存者，他们面临着终身的认知，情感和社会缺陷。虽然病理改变（细胞死亡，轴突损伤，反应性神经胶质增生和炎症）后闭合性脑损伤似乎是相似的成熟和未成熟的大脑，临床和动物研究开始证明，在急性和慢性创伤后时期的致病机制是相当不同的两个年龄。第二个问题是，急性神经保护策略，临床试验和临床前研究的支柱，是集中在一个单一的“灵丹妙药”的方法，尽管致病机制的众多，设置在临床试验失败的阶段。因此，本提案旨在填补这两个空白的TBI文献中使用一个年龄合适的，临床相关的模型，儿科TBI和测试是否两个策略，每一个旨在限制明显不同的病理途径，当结合起来，将改善功能的结果。选择17日龄大鼠作为实验动物，其神经功能相当于3-4岁幼儿。在目前的建议中，这两种策略的选择来自于初步观察，即钙调磷酸酶抑制剂和亲免疫素配体FK 506，减弱创伤性轴突损伤后闭合性脑损伤在未成年大鼠。在单独的实验中，观察到抗炎和抗凋亡三肽（Glypromate）-从胰岛素样生长因子的N-末端内源性衍生-减少小胶质细胞活化、组织钙蛋白酶活化和伴随的神经变性。使用生物化学、免疫组织化学、电生理学和行为分析的组合，待检验的假设是，FK 506通过抑制钙调神经磷酸酶介导的神经丝致密化和减少轴突损伤，与Glypromate（将抑制小胶质细胞活化、减少细胞因子合成和减少神经变性）联合使用，将共同减少脑损伤未成熟大鼠的急性和慢性学习和记忆缺陷。 公共卫生相关性：脑创伤对人口中最年轻的部分是一个严重的健康问题。幸存者面临着终身残疾，从社会和情感问题到学习和记忆缺陷。目前还没有治疗方法可以缓解这些缺陷。该提案旨在评估限制多种退行性变化的方法，以改善未成熟动物闭合性脑损伤后的行为功能。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality in infants and children under the age of 4. As in the case of older children and adults, the spectrum of injury severity spans the gamut from mild to severe, with mild-moderate injured patients being the predominant population. In addition, increased efficacy of supportive neurointensive care has significantly reduced the mortality. Collectively, these phenomena result in an increasing number of survivors of TBI, who are faced with suffering life-long cognitive, emotional and social deficits. Although the pathologic alterations (cell death, axonal injury, reactive gliosis and inflammation) following closed head injury appears to be similar in both the mature and immature brains, clinical and animal studies are beginning to demonstrate that the pathogenic mechanisms in the acute and chronic post-traumatic periods are fairly dissimilar between the two ages. A second problem is that acute neuroprotective strategies, the mainstay of clinical trials and pre-clinical studies, are focused on a single "magic bullet" approach despite the multitude of pathogenic mechanisms, setting the stage for failure in clinical trials. This proposal therefore seeks to fill these two gaps in the TBI literature by using an age-appropriate, clinically-relevant model of pediatric TBI and testing whether two strategies, each aimed at limiting distinctly separate pathologic pathways, when combined, will improve functional outcome. The 17-day-old rat which is neurologically equivalent to 3-4-year-old toddler is the animal of choice. The choice of the two strategies in the current proposal arises from preliminary observations that the calcineurin inhibitor and immunophilin ligand, FK506, attenuates traumatic axonal injury following closed head injury in immature rats. In separate experiments, it was observed that the anti-inflammatory and anti-apoptotic tripeptide, Glypromate - derived endogenously from the N-terminus of insulin-like growth factor - reduced microglial activation, tissue calpain activation and attendant neurodegeneration. Using a combination of biochemical, immunohistochemical, electrophysiological and behavioral analyses, the hypothesis to be tested is that FK506, by inhibiting calcineurin-mediated neurofilament compaction and decreasing axonal injury, in combination with Glypromate which will inhibit microglial activation, decrease cytokine synthesis and reduce neurodegeneration, will together reduce acute and chronic learning and memory deficits in the brain-injured immature rat. PUBLIC HEALTH RELEVANCE: Brain trauma to the youngest section of the population is a serious health problem. Survivors are faced with life-long disabilities ranging from social and emotional problems to learning and memory deficits. Currently no treatment exists that can alleviate these deficits. This proposal seeks to evaluate approaches that will limit the multiple degenerative changes in order to improve behavioral function following closed head injury in an immature animal.