Pathology-directed combination therapy for pediatric TBI

描述(申请人提供)：创伤性脑损伤(TBI)是导致4岁以下婴儿和儿童发病和死亡的主要原因之一。与年龄较大的儿童和成年人的情况一样，损伤的严重程度从轻度到重度不等，以轻到中度损伤的患者为主。此外，支持性神经重症监护的疗效提高显著降低了死亡率。总体而言，这些现象导致越来越多的脑外伤幸存者面临终身认知、情感和社会缺陷。尽管闭合性脑损伤后的病理改变(细胞死亡、轴突损伤、反应性胶质增生和炎症)在成熟和未成熟的脑中似乎是相似的，但临床和动物研究开始证明，两个年龄段的急性和慢性创伤后阶段的致病机制相当不同。第二个问题是，急性神经保护策略是临床试验和临床前研究的支柱，尽管致病机制多种多样，但它们专注于单一的“魔弹”方法，为临床试验的失败铺平了道路。因此，这项建议试图通过使用适合年龄的、临床相关的儿童脑损伤模型来填补脑损伤文献中的这两个空白，并测试两种策略，每种策略的目的都是限制明显不同的病理途径，当组合在一起时，是否会改善功能结果。17天大的老鼠在神经学上相当于3-4岁的蹒跚学步的孩子，它是首选的动物。在目前的建议中选择这两种策略是因为初步观察到钙调神经磷酸酶抑制剂和免疫亲和素配体FK506可以减轻未成熟大鼠闭合性脑损伤后的创伤性轴索损伤。在单独的实验中，观察到从胰岛素样生长因子N端内源性衍生的抗炎和抗凋亡三肽--甘氨酸会减少小胶质细胞的激活、组织钙蛋白酶的激活和伴随的神经变性。结合生化、免疫组织化学、电生理和行为分析，将被检验的假设是，FK506通过抑制钙调神经磷酸酶介导的神经丝紧致和减少轴突损伤，与将抑制小胶质细胞激活、减少细胞因子合成和减少神经退化的甘氨酸盐联合使用，将共同减少脑损伤未成熟大鼠的急性和慢性学习和记忆障碍。 公共卫生相关性：对人口中最年轻的部分来说，脑损伤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。目前还没有可以缓解这些缺陷的治疗方法。该建议旨在评估限制多种退行性改变的方法，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.