NEUROTRANSMITTER INDUCED NEUROTOXICITY IN TRAUMATIC BRAIN INJURY MODELS

药理学研究表明，阻断谷氨酸受体 及其在局灶性和全脑缺血模型中的释放，和 剪切损伤（如流体冲击），已经显示出更大和更多 因此，与任何其他测试机制相比， 远了 谷氨酸拮抗剂的临床试验正在进行中， 严重的头部创伤 尽管如此，谷氨酸在 脑缺血和剪切损伤的病理生理学， 不太了解。 与其他病理生理机制相反， 谷氨酸盐的存在可以在急性缺血期间被证明， 剪切损伤后的电生理和代谢效应 脑组织的损伤可以被证明。 然而，一个核心的矛盾仍然存在：谷氨酸水平表明， 在动物模型中以及在头部后的人类微透析研究中， 伤害，至少比浓度低一个数量级 需要破坏老鼠的完整皮层。 这种差异存在 即使当允许微透析探针回收时 效率和细胞外空间中的弯曲因子。 因此，有必要假定其他机制必须发挥作用， 与谷氨酸协同作用，以放大其 缺血和剪切损伤中的神经毒性作用。 因此，该子项目的目的是应用新的体内模型， “纯”谷氨酸神经毒性创伤，并测试的因素， 加重或减轻创伤中谷氨酸的神经毒性作用 和局部缺血。 该模型作为潜在的筛选工具的实用性 将对药物和药物组合进行评价。 新药和 在该模型中证明有效的组合可以继续进行 对于流体冲击模型中的行为和组织学评价， 体重下降以及局部和全身缺血。

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.