Pathology-directed combination therapy for pediatric TBI

摘要 创伤性脑损伤（TBI）是婴儿发病率和死亡率的主要原因之一， 4岁以下儿童。与年龄较大的儿童和成人一样， 从轻度到重度，轻中度受伤的患者是主要人群。在 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创伤性脑损伤幸存者面临痛苦 终身认知、情感和社交缺陷。虽然病理变化（细胞死亡，轴突损伤， 反应性神经胶质增生和炎症）在闭合性脑损伤后的成熟和 临床和动物研究开始证明，在不成熟的大脑中， 急性和慢性创伤后时期在这两个年龄段之间是相当不同的。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支柱， 尽管有多种致病机制，但“灵丹妙药”方法为临床治疗失败奠定了基础。 审判因此，该提案试图通过使用适合年龄的， 儿童TBI的临床相关模型，并测试是否有两种策略，每种策略的目的是限制不同的 单独的病理途径在组合时将改善功能结果。17天大的老鼠 神经学上等同于3-4岁幼儿的动物是首选动物。这两种策略的选择， 目前的建议来自于对钙调磷酸酶抑制剂和亲免素配体的初步观察， FK 506减轻未成年大鼠闭合性脑损伤后的创伤性轴索损伤。分开的 在实验中，观察到抗炎和抗凋亡三肽，Glypromate -衍生的 内源性来自胰岛素样生长因子的N-末端-减少的小胶质细胞活化，组织钙蛋白酶 激活和伴随的神经变性。结合生化免疫组织化学， 电生理学和行为学分析，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组合， 抑制小胶质细胞活化、减少细胞因子合成和减少神经变性，将共同减少 急性和慢性学习记忆障碍的脑损伤的未成年大鼠。

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.