Protein Kinase C Isozymes in Stroke-Therapeutic Target?

描述(申请人提供)：这个国家每年发生超过50万例中风，导致严重的残疾和死亡。目前只有一种治疗方法--重组组织型纤溶酶原激活剂(rt-PA)--被批准用于中风。然而，只有大约3%的患者接受治疗，可能是因为治疗的时间窗口很短(3小时或更少)。因此，非常需要有效的神经保护剂，既可以单独给药，也可以与溶栓药物联合使用。 此外，预防性神经保护用法可能适用于某些临床环境。仅在美国，每年就有60万成年人和1.2万儿童接受体外循环心脏直视手术，在此期间大脑处于缺血期。尽管外科手术的进步和缺血事件的缩短，中枢神经系统功能障碍仍然是这些患者发病率和死亡率的主要原因。由于这些患者的缺血性损伤的确切时间是提前知道的，因此在手术前使用保护大脑免受缺血再灌注损伤的药物进行预治疗，有可能显著减少心肌损伤。 我们的假设是，选择蛋白激酶C(PKC)同工酶在大脑对缺血性损伤反应的不同阶段起着重要的(积极和/或消极的)作用。 利用我们开发的同工酶特异性抑制物和激活肽，我们计划；确定脑缺血后哪些PKC同工酶被激活以及何时发生，并确定这些同工酶的抑制或激活是否可以提供对脑缺血再灌注损伤的保护。 这些研究将证明体内递送PKC调节多肽治疗中枢神经系统缺血再灌注损伤的有效性。如果这种治疗被发现是有效和安全的，这些PKC活性的多肽调节剂可能对人类中风和脑缺血的治疗有用。

DESCRIPTION (provided by applicant): Over 500,000 strokes occur in this country annually, causing significant disability and death. Only one treatment, recombinant tissue plasminogen activator (rt-PA), is currently approved for stroke. However, just about 3% of the patients receive it, probably because the time-window for therapy is brief (3 hours or less). Therefore, there is a great need for effective neuroprotective agents that could be given alone or in conjunction with thrombolytic agents. Furthermore, prophylactic neuroprotective use may be indicated in certain clinical settings. Each year, in the United States alone, 600,000 adults and 12,000 children undergo open heart operations utilizing cardiopulmonary bypass, during which the brain is subjected to periods of ischemia. Despite advances in surgical procedures and shortening of the ischemic event, CNS dysfunction remains a leading cause of morbidity and mortality in these patients. Because the exact timing of the ischemic insult is known ahead of time in these patients, the potential exists to significantly reduce myocardial damage by pre-treatment with agents that protect the brain from ischemia-reperfusion damage prior to surgery. Our HYPOTHESIS is that select protein kinase C (PKC) isozymes play an important (positive and/or negative) role in the various stages of response of the brain to ischemic insult. Using isozyme-specific inhibitor and activator peptides that we have developed, we plan to; determine which PKC isozymes are activated following cerebral ischemia and when does that occur, and determine whether inhibition or activation of these isozymes can provide protection from ischemic reperfusion damage to the brain. These studies will demonstrate the effectiveness of in vivo delivery of PKC regulating peptides for the treatment of ischemic reperfusion injury of the CNS. Should the treatment be found efficacious and safe, these peptide regulators of PKC activity may be useful for the treatment of stroke and brain ischemia in humans.