DESCRIPTION: Subarachnoid Hemorrhage (SAH) is a form of stroke that occurs in nearly 40,000 patients each year in the United States. Despite advances in early diagnosis and management, SAH remains a frequent cause of death and disability. In particular, vasospasm is the most common medical complication of subarachnoid hemorrhage, and often leads to further stroke and added death and disability. This disability is the result of ischemic injury due to the lack of oxygen transport to the brain following vasospasm. Although vasospasm remains the most important cause of mortality and neurological morbidity in patients initially surviving aneurismal SAH, no effective treatment has been developed to reduce the frequency of, or to reduce the damage from this complication. Cognosci has recently developed novel apoE-based therapeutics that cross the blood brain barrier and exert neuroprotective and anti-inflammatory activities. One of these compounds, COG1410 has been evaluated in a clinically relevant mouse model of SAH increased survival rates, reduced the occurrence of vasospasm and improved neurological outcome (GAO Et Al. 2006, Mesis et al. 2006). We now propose to further evaluate COG1410 for treatment of SAH by determining if the compound will reduce vasospasm in a rabbit model of vasospasm and to investigate a possible mechanism by which this action may occur. We further propose to evaluate COG1410 in two in vitro models to assess genotoxicity and cardiotoxicity. Successful completion of these studies will provide proof of principle that COG1410 has the desired characteristics in inhibition of vasospasm following SAH and that the compound is free from toxic effects that are routinely evaluated using in vitro assays. This proof of principle with then for the basis for initiation of toxicology studies during the Phase II granting period that will be designed to determine the in vivo safety profile for COG1410 so that an Investigational New Drug (IND) application can be filed with the FDA to initiate human clinical trials for this important orphan indication. [unreadable] [unreadable] [unreadable]