Biochemical Mechanisms of Cerebral Vasospasm

描述(申请人提供)：血管痉挛是蛛网膜下腔出血(SAH)患者迟发性缺血性中风的常见原因。在这个项目中，我们将评估导致蛛网膜下腔出血诱导的脑血管痉挛的分子(S)。血管痉挛的原因在很大程度上尚不清楚，但已被认为是由于出血性脑脊液中的血管活性分子所致。我们在SAH患者的脑脊液中发现了胆红素氧化产物(BOX)，推测BOX是一种可引起脑血管痉挛的磷酸酶抑制剂。目前已鉴定出三种结构上相关的分子。这些分子在体内和体外对血管产生持久的收缩作用，这与SAH患者脑脊液中血管痉挛的持久作用惊人地相似。 我们认为，平滑肌蛋白磷酸酶抑制会导致血管痉挛延长。此外，正是这种磷酸酶抑制剂BOX会在蛛网膜下腔出血后的患者中产生长时间的血管痉挛。在使用颅窗技术的目标#1和#2中，我们将检查BOX引起的大鼠脑血管痉挛的时间进程，并将评估单个BOX的效力。将在14天内研究血管收缩的程度，并检查大脑是否有损伤的证据。在目标#3中，我们将展示BOX抑制磷酸酶，并在体外使用猪基底动脉导致血管痉挛。 该项目的长期目标是确定血管痉挛的分子原因(如胆红素氧化产物、磷酸酶抑制)，以便为这种脑血管疾病开发有效的诊断、治疗和预防方法。

DESCRIPTION (provided by applicant): Vasospasm is a frequent cause of delayed ischemic stroke in subarachnoid hemorrhage (SAH) patients. In this project we will evaluate the molecule(s) that are responsible for causing SAH-induced cerebral vasospasm. The cause of the vasospasm is largely unknown but it has been suggested to be due to a vasoactive molecule in the hemorrhagic CSF. We have found that bilirubin oxidation products (BOXes) are found in the CSF of SAH patients and propose that the BOXes are phosphatase inhibitors that can cause cerebral vasospasm. There have been three structurally related molecules identified. These molecules produce prolonged contractile effects on the vessels in vivo and in vitro that are strikingly similar to the prolonged vasospasm seen from the CSF of SAH patients with vasospasm. We suggest that smooth muscle protein phosphatase inhibition causes prolonged vasospasm. Moreover it is the BOXes that are the phosphatase inhibitors that produce prolonged vasospasm in patients following subarachnoid hemorrhage. In Aims #1 and #2 using cranial window technique, we will examine the time course of cerebral vasospasm in rats caused by the BOXes, and will assess the potency of the individual BOXes. The degree of vascular constriction will be studied over 14 days and the brain examined for evidence of damage. In Aim #3 we will show that BOXes inhibit phosphatases and that this leads to vasospasm using porcine basilar artery in vitro. The long-term goal for this project is to define the molecular causes of vasospasm (such as bilirubin oxidation products, phosphatase inhibition) in order to develop effective diagnostic, therapeutic and preventative approaches for this cerebral vascular disease.