NEUROTRANSMITTER INDUCED NEUROTOXICITY IN TRAUMATIC BRAIN INJURY MODELS

药理学研究表明，谷氨酸受体的阻断 在局灶性和全局性脑缺血模型中释放，以及 剪切性损伤(如液体撞击)，已表现出较大和较多 一致的神经保护效果超过任何其他这样测试的机制 远远的。谷氨酸拮抗剂的临床试验目前正在进行中 严重的头部创伤。然而，谷氨酸在体内的作用 脑缺血和剪切伤的病理生理学 人们对此知之甚少。与其他病理生理机制不同， 谷氨酸的存在可以在急性缺血和 剪切伤后的电生理和代谢效应 对脑组织的影响可能会被证实。 然而，一个中心悖论仍然存在：谷氨酸的水平显示 在动物模型中和在人类头部后的微透析研究中 伤害，至少比浓度低一个数量级 需要破坏大鼠完整的皮质。这种差异是存在的 即使考虑到微透析探头回收 效率和细胞外空间中的曲折因素。 因此，有必要假定其他机制必须采取行动 与谷氨酸协同作用，以放大其 对脑缺血和剪切损伤均有神经毒性作用。 因此，这个子项目的目的是应用新的活体模型 纯谷氨酸对创伤的神经毒性，并测试哪些因素 加重或改善谷氨酸在创伤中的神经毒性作用 和脑缺血。模型作为一种潜在的筛选工具的实用性 将对药物和药物组合进行评估。新药和 在这个模型中被证明是有效的组合，然后可以继续进行 对于流体敲击模型的行为和组织学评估， 体重下降，以及局灶性和全局性缺血。

Pharmacological studies have shown that blockade of glutamate receptors and its release in models of focal and global cerebral ischemia, and shear injury (such as fluid percussion), have shown larger and more consistent neuroprotective efficacy than any other mechanism tested thus far. Clinical trials with glutamate antagonists are now in progress for severe head trauma. Nevertheless, the role of glutamate in the pathophysiology of both cerebral ischemia and shear injury, remains poorly understood. In contrast to other pathophysiological mechanisms, the presence of glutamate can be demonstrated during acute ischemia and after shearing injury, and its electrophysiological and metabolic effects upon cerebral tissue may be demonstrated. A central paradox however, remains: the levels of glutamate demonstrated in animal models and also in human microdialysis studies after head injury, are at least one order of magnitude lower than the concentrations needed to damage the intact cortex in the rat. This discrepancy exists even when allowances are made for microdialysis probe recovery efficiencies, and tortuosity factors in the extracellular space. It is therefore necessary to postulate that other mechanisms must act synergistically together with glutamate, in order to magnify its neurotoxic effects in both ischemia, and shearing injury. The purposes of this subproject is thus to apply new in vivo models of 'pure' glutamate neurotoxicity to trauma, and to test for factors which exacerbate or ameliorate the neurotoxic effects of glutamate in trauma and ischemia. The utility of the model as a potential 'screening tool ' for drugs and drug combination will be evaluated. New drugs and combinations shown to be efficacious in this model, can then go forward for behavioral and histological evaluation in models of fluid percussion, weight drop, and focal and global ischemia.