IONIC FLUXES AND NEURONAL DYSFUNCTION IN BRAIN INJURY

创伤性脑损伤治疗的一个主要目标是提供一种理想的 恢复代谢紊乱的神经细胞的环境，但 不是机械的和不可逆转的损坏。这项建议的目的是 阐明这种神经细胞代谢紊乱的机制 细胞遭受亚致命性创伤。我们的初步研究 揭示了巨大的离子通量是在这些区域发生的重大事件 细胞。我们的初步研究还表明，不加区别地释放 神经递质，特别是兴奋性氨基酸，以及递质- 依赖的离子通道在产生这些离子事件中起着至关重要的作用。 神经递质释放对离子通透性的影响 神经元是可兴奋的细胞的特征。因此，这些现象 与体内的任何其他细胞相比，是神经细胞所独有的。 有很多理由可以预期，即使是短暂的离子 扰动引发包括乳酸在内的长期代谢紊乱 积累。我们之前的观察表明，乳酸盐肯定会 脑脊液和脑组织在最初的60分钟内增加。 在创伤性脑损伤之后。因为乳酸盐的有害影响 缺血性脑损伤中的蓄积已被反复证明， 乳酸的积累很可能与导致 受到创伤的神经细胞更容易受到第二次侮辱。 因此，这项提议的近期目标是确定：(1) 霉菌至中度创伤后离子熔剂的存在和程度 脑损伤：(2)大量离子通量的机制：和(3)它们 在乳酸积累过程中的重要性。我们将广泛地 利用脑微透析技术回答其中提出的问题 求婚。这项技术使我们能够监测离子环境和其他 同时细胞外间隙(ECS)的神经化学变化和 提供了一种将各种药物注入ECS的手段。如果 假设被证明是正确的，将会取得重大进展 理解创伤所特有的代谢紊乱序列 从受伤的那一刻开始的脑部侮辱。长期目标 我们基于这里提出的实验数据所做的研究如下： (1)确定创伤后乳酸蓄积的机制 脑损伤；以及(2)确定理想的ECS环境，以保护脑损伤 因乳酸蓄积而受损的神经细胞。最终这就是 信息将导致创伤性脑损伤的治疗得到改善。

A major goal of therapies for traumatic brain injury is to provide an ideal milieu for recovery of neuronal cells which are metabolically deranged but not mechanically and irreversibly damaged. The purpose of this proposal is to delineate the mechanisms of such metabolic derangements of neuronal cells subjected to sublethal traumatic injury. Our preliminary studies revealed that massive ionic fluxes are a major event taking place in these cells. Our preliminary studies also suggest that indiscriminate release of neurotransmitter, especially excitatory amino acids, and transmitter- dependent ion channels play a vital role in producing these ionic events. Changes in ionic permeability in response to neurotransmitter release are characteristic of the neuron as an excitable cell. Thus, these phenomena are unique to neuronal cells as compared with any other cell in the body. There are a number of reasons to expect that even transient ionic perturbation triggers long-lasting metabolic derangements including lactate accumulation. Our previous observation indicated that lactate definitely increases in CSF as well as brain tissue during the initial 60 min. following traumatic brain injury. Since detrimental effects of lactate accumulation in ischemic brain injury have repeatedly been demonstrated, lactate accumulation is likely to be related to the mechanisms that render the traumatized neuronal cells more vulnerable to a second insult. Thus, the immediate goals of this proposal are to determine: (1) the existence and extent of ionic fluxes following mold to moderate traumatic brain injury: (2) the mechanism of the massive ionic fluxes: and (3) their importance in the process of lactate accumulation. We will extensively utilize brain microdialysis technique to answer the question posed in this proposal. This technique enables us to monitor ionic environment and other neurochemical changes in the extracellular space (ECS) simultaneously and provides a means for administering various drugs into the ECS. If the hypotheses are proven to be true, a major advance will have been made in understanding the sequence of metabolic derangements unique to traumatic brain insult which begins from the moment of injury. The long-term goals of our research based on the data from the experiments proposed here are: (1) to determine the mechanisms of lactate accumulation following traumatic brain injury; and (2) to identify the ideal ECS milieu for protection of the traumatized neuronal cells from lactate accumulation. Ultimately this information would lead to improved treatment of traumatic brain injury.