HYPOTHERMIA AND TRAUMA

体温过低和创伤

• 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
• 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

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.

亚低温疗法作为一种治疗方法受到了广泛的关注 头部及多个系统受伤的外伤患者 受伤。 外伤后脑缺血经常发生 人类头部受伤后的结果显着恶化。 然而， 尚未在创伤性脑损伤 (TB) 模型中评估体温过低 伴有继发性缺血。 我们已经证明，受创伤的大脑 在流体冲击 TBI 啮齿动物模型中对缺血过敏（FP- TBI）伴有继发性和几乎完全的前脑缺血。 我们的研究 还表现出海马对创伤后前脑缺血的超敏反应 FP-TB1 后 1 至 24 小时，部分由兴奋性毒性介导 机制。 实验研究表明，中度低温（30-33 摄氏度）可以通过减少兴奋毒性来提供神经保护 损害。 我们为兴奋性毒性过程提供了以下证据 FP-TB1 后：1) 毒蕈碱和 NMDA 受体拮抗剂减弱 外伤后缺血性超敏反应； 2）增加大脑兴奋性 氨基酸 (EAA) 暴露发生在 TBI 和继发性缺血期间； 3） 增强海马代谢受体对乙酰胆碱的敏感性， 谷氨酸和血清素，如激动剂诱导的增加所推断的 多磷酸肌醇 (PI) 更新，发生在 TBI 后； 4）显着 TBI 后总蛋白激酶 C (PKC) 下调； 5） 海马显微注射星形孢菌素（一种丝氨酸-苏氨酸蛋白激酶） 抑制剂）或金雀异黄酮（酪氨酸激酶抑制剂）都会减弱 增强创伤后 CA1 缺血性神经元死亡。 我们相信 创伤后 PKC 下调可能是造成这种增强的原因 信号转导。 信号增强的两个潜在后果 这些受体家族的转导在突触前得到增强 神经递质释放和突触后神经递质敏感性 可能会受到低温调节的功能障碍。 我们建议：a) 创伤后神经递质和缺血性 过敏症是由于谷氨酸受体受损而发生的 继发于异常蛋白激酶激活的效应子下调， 特别是 PKC； b) 治疗性减少创伤后应激反应 神经递质和缺血性超敏反应可以通过中等程度来实现 低温。 我们将测试是否：a）增强创伤后 神经递质相关受体耦合信号转导有助于 通过操纵上调来治疗创伤后缺血性超敏反应 受体系统与各种中低温应用之前或 外伤后； b) 创伤后蛋白激酶活性的改变有助于 改变创伤后受体偶联信号转导 之前或之后使用各种中低温应用进行操作 创伤。 这些假设将通过施用适度的 TBI 之前或之后的低温和评估海马 CA1 神经元 死亡、空间记忆、海马 EAA 水平、谷氨酸激动剂诱导的 PI PKC 同种型的水解和 SDS-PAGE 分离/免疫印迹。