Stroke is the third leading cause of death and long-term disability in the Western population. The results of a similar injury are worse in the adults than in young people, but the mechanisms underlying this difference are unknown. My main goal here is to find out the importance of clinically relevant PGI2 as a modulator of the inflammatory process, in global cerebral ischemia mouse model in old and young mice to address this question. An interdisciplinary research team with neurologist expertise in molecular and behavioral neuroscience and neuropathologist will address the hypotheses that increased inflammatory response due to global cerebral ischemia in older prostacyclin receptor ( PGI2) (IP) KO will worsen the learning and memory performance, decrease regional cerebral blood flow (rCBF), increase leukocyte infiltration and hippocampal neuronal cell death as compared to WT mice. The experiments test the specific hypothesis that in old mice, an enhanced inflammatory response results in decrease in phospho CREB and CREB levels after global cerebral ischemia. Preliminary data this hypothesis by demonstrating reduced learning and memory performance and increased hippocampal cell death in IP KO mice as compared to WT mice.
Four specific aims are proposed to test these hypotheses: 1) Determine whether genetic deletion of PGI2 (IP) receptor will aggravate neurobehavioral deficit and neuronal cell death in C57Bl6 older mice (12-15 months old) as compared to younger mice (2-3 months old). 2) Determine whether attenuated absolute rCBF and increased leukocyte infiltration will be observed in older IP-/- as compared to young mice as compared to their controls. 3) Determines whether IP agonists improve and antagonists reduce learning and memory performance after global cerebral ischemia in WT mice. 4) Determine the neuronal cell death by performing immunohistochemistry and find out the mechanism of actions by investigating the phospho-CREB and CREB level at different time points- 1h, 3h and 1, 4 and 7d after global cerebral ischemia. Development of these novel clinically relevant drugs could provide a new therapeutic strategy against global cerebral ischemia and potentially other neurodegenerative disorders. This research proposal will have direct pre-clinical importance by developing therapeutic PGI2 (IP) receptor stimulating drugs to improve learning and memory and controlling brain damage induced by cardiac arrest in elderly people.
Stroke and brain damage following cardiac arrest are the leading causes of death in United States, accounting for an estimated 325,000 deaths each year. The increasing rate and outcomes of a stroke or cardiac arrest is likely to be worsening with the aging of the population, but the mechanisms underlying this difference are unknown. This research proposal will test the importance of PGI2 (IP) receptor drugs to potentially improve learning and memory and controlling brain damage induced by global ischemic conditions, in young and aged preclinical models.