HYPOTHERMIA AND TRAUMA

体温过低和创伤

基本信息

批准号：
2703096
负责人：
LARRY W JENKINS
金额：
$ 1.1万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-05-01 至 1998-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2703096
关键词：
NMDA receptors brain injury cell death cerebral ischemia /hypoxia disease /disorder model enzyme activity excitatory aminoacid glutamate receptor hippocampus induced hypothermia isozymes laboratory rat memory neuroprotectants neurotoxicology nonhuman therapy evaluation phosphatidylinositols protein kinase receptor coupling receptor expression receptor sensitivity western blottings

NMDA receptors brain injury cell death cerebral ischemia /hypoxia disease /disorder model enzyme activity excitatory aminoacid glutamate receptor hippocampus induced hypothermia isozymes laboratory rat memory neuroprotectants neurotoxicology nonhuman therapy evaluation phosphatidylinositols protein kinase receptor coupling receptor expression receptor sensitivity western blottings

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项目摘要

Hypothermia therapy has received considerable attention as a treatment for trauma patients who sustain head injuries as well as multiple system injury. Posttraumatic cerebral ischemia occurs frequently and significantly worsens outcome after human head injury. However, hypothermia has not been assessed in a model of traumatic brain injury (TB) with secondary ischemia. We have shown that the traumatized brain is hypersensitive to ischemia in a rodent model of fluid-percussion TBI (FP- TBI) with secondary and nearly complete forebrain ischemia. Our studies also show hippocampal hypersensitivity to posttraumatic forebrain ischemia for 1 to 24 hours after FP-TB1, which is mediated, in part, by excitotoxic mechanisms. Experimental studies suggest that moderate hypothermia (30-33 degree centrigrade) may provide neuroprotection by decreasing excitotoxic damage. We have provided the following evidence for excitotoxic processes after FP-TB1: 1) muscarinic and NMDA receptor antagonists attenuate posttraumatic ischemic hypersensitivity; 2) increased brain excitatory amino acid (EAA) exposure occurs during TBI and secondary ischemia; 3) enhanced hippocampal metabotropic receptor sensitivity to acetylcholine, glutamate, and serotonin, as inferred by increased agonist-induced polyphosphoinositide (PI) turnover, occurs after TBI; 4) significant downregulation of total protein kinase C (PKC) occurs after TBI; 5) hippocampal microinjected staurosporine (a serine-threonine protein kinase inhibitor) or genistein (a tyrosine kinase inhibitor) both attenuate enhanced posttraumatic CA1 ischemic neuronal death. We believe that posttraumatic PKC downregulation may be responsible for this enhanced signal transduction. Two potential consequences of increased signal transduction of these receptor families are enhanced presynaptic neurotransmitter release and postsynaptic neurotransmitter sensitivity dysfunction that may be modulated by hypothermia. We propose that: a) posttraumatic neurotransmitter and ischemic hypersensitivity occur as the result of impaired glutamate receptor- effector downregulation secondary to aberrant protein kinase activation, especially by PKC; b) a therapeutic reduction of posttraumatic neurotransmitter and ischemic hypersensitivity can be achieve with moderate hypothermia. We will test whether: a) enhanced posttraumatic neurotransmitter-linked receptor-coupled signal transduction contributes to post traumatic ischemic hypersensitivity by manipulating upregulated receptor systems with various moderate hypothermia applications before or after trauma; b) altered posttraumatic protein kinase activity contributes to altered posttraumatic receptor-coupled signal transduction by manipulation with various moderate hypothermia applications before or after trauma. These hypotheses will be tested by administering moderate hypothermia before or after TBI and evaluating hippocampal CA1 neuronal death, spatial memory, hippocampal EAA levels, glutamate agonist-induced PI hydrolysis, and SDS-PAGE separation/immunoblots of PKC isoforms.

体温过低的疗法已受到大量关注作为治疗受伤以及多个系统的创伤患者受伤。创伤后脑缺血经常发生，并且人头损伤后的结果显着恶化。然而，尚未在创伤性脑损伤模型（TB）中评估体温过低伴有次级缺血。我们已经表明，受创伤的大脑是在流体渗透TBI的啮齿动物模型中对缺血性高敏性（FP- tbi）含有继发性和几乎完全完整的前脑缺血。我们的研究还显示出对创伤后前脑缺血的海马过敏性 FP-TB1之后的1至24小时，部分是由兴奋性毒性介导的机制。实验研究表明中度低温（30-33 学位偏rigrade）可以通过降低兴奋性毒性来提供神经保护作用损害。我们提供了以下兴奋毒过程的证据 FP-TB1：1）毒蕈碱和NMDA受体拮抗剂减弱创伤后缺血性超敏反应； 2）增加大脑兴奋性在TBI和继发性缺血期间，氨基酸（EAA）暴露发生。 3）增强海马代谢受体对乙酰胆碱的敏感性，谷氨酸和5-羟色胺，由激动剂诱导的增加 TBI之后发生多磷酸肌醇（PI）周转。 4）重要 TBI后发生总蛋白激酶C（PKC）的下调； 5）海马显微注射的星形孢菌素（丝氨酸 - 硫代蛋白激酶抑制剂）或染料木黄酮（酪氨酸激酶抑制剂）均减弱增强创伤后CA1缺血性神经元死亡。我们相信创伤后的PKC下调可能是对这一增强的负责信号转导。信号增加的两个潜在后果这些受体家族的转导增强了突触前神经递质释放和突触后神经递质灵敏度可能由体温过低调节的功能障碍。我们建议：a）创伤后神经递质和缺血性高敏性由于谷氨酸受体受损而发生效应子下调继发于异常蛋白激酶激活，特别是PKC； b）创伤后的治疗性降低神经递质和缺血性超敏反应可以通过中等低温。我们将测试是否：a）创伤后增强神经递质连接受体偶联信号转导导入有助于通过操纵上调的外伤性缺血性超敏反应在或创伤后； b）创伤后蛋白激酶活性改变了改变创伤后受体耦合的信号转导用各种中度低温应用程序进行操作之前或之后创伤。这些假设将通过中等测试 TBI之前或之后的体温过低并评估海马CA1神经元死亡，空间记忆，海马EAA水平，谷氨酸激动剂引起的PI PKC同工型的水解和SDS-PAGE分离/免疫印迹。