Pathology-directed combination therapy for pediatric TBI

摘要 创伤性脑损伤(TBI)是导致婴儿和儿童死亡的主要原因之一。 4岁以下的儿童。与年龄较大的儿童和成年人的情况一样，伤害的严重程度跨度很大 伤情范围从轻到重，以轻、中度受伤患者为主。在……里面 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。 总体而言，这些现象导致越来越多的脑外伤幸存者面临苦难。 终身认知、情感和社会缺陷。尽管病理改变(细胞死亡，轴突损伤， 反应性胶质细胞增多症和炎症)闭合性脑损伤后，成熟和 未成熟的大脑、临床和动物研究开始证明其致病机制。 急性和慢性创伤后时期在这两个年龄段是相当不同的。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主要内容，主要集中在单一的 尽管致病机制多种多样，但仍采用“神奇子弹”的方法，为临床失败铺平了道路 审判。因此，该建议试图通过使用适合年龄的、 儿童颅脑损伤的临床相关模型及两种策略的检测，每种策略的目的都是明确限制 单独的病理途径，当组合在一起时，将改善功能结果。这只17天大的老鼠是 在神经学上相当于3-4岁的幼儿是首选的动物。这两种策略的选择 目前的建议源于初步观察到的钙调神经磷酸酶抑制剂和免疫亲和素配体， FK506减轻幼年大鼠闭合性脑损伤后创伤性轴索损伤。在单独的 实验中，观察到了抗炎和抗细胞凋亡的三肽--氨基琥珀酸衍生物 内源性来自胰岛素样生长因子N端的小胶质细胞激活减少，组织钙蛋白 激活和伴随的神经退行性变。使用生化，免疫组织化学， 电生理和行为分析，需要检验的假设是FK506，通过抑制钙调神经磷酸酶- 介导的神经丝致密和减轻轴突损伤，与将 抑制小胶质细胞的激活，减少细胞因子的合成，减少神经变性，将共同减少 脑损伤幼鼠的急性和慢性学习记忆障碍。

Abstract 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 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 these 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 rat. 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, electrophysiologic 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.