Biochemical Mechanisms of Cerebral Vasospasm

描述（由申请人提供）：血管痉挛是蛛网膜下腔出血（SAH）患者迟发性缺血性卒中的常见原因。在这个项目中，我们将评估导致sah诱导的脑血管痉挛的分子。血管痉挛的原因尚不清楚，但据推测可能与出血性脑脊液中的血管活性分子有关。我们发现胆红素氧化产物（box）存在于SAH患者的脑脊液中，并提出box是引起脑血管痉挛的磷酸酶抑制剂。已经鉴定出三种结构相关的分子。这些分子在体内和体外对血管产生延长的收缩作用，这与SAH患者伴血管痉挛的脑脊液中观察到的延长的血管痉挛惊人地相似。

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.