Intracerebral hemorrhage (ICH) is the stroke subtype with the highest death rate and poorest prognosis in survivors. Presently, there are no effective treatments. The cellular and molecular mechanisms through which intracerebral blood induces brain injury are poorly understood. Rapidly initiated inflammatory responses involving cytokine cascades likely contribute to vasogenic edema, tissue damage and morbidity after ICH. Our overall goal in this proposal is to define the role of proinflammatory cytokine expression and downstream target gene responses in ICH induced injury to perihematomal white and gray matter. The rationale for these studies is supported by our preliminarily data demonstrating rapid (0.5 hr) activation of nuclear factor kappaB (NF-kB), the transcription factor that regulates many inflammatoryresponse genes. In addition, elevated expression of pro-inflammatory cytokine genes (IL-I beta, TNF-a, IL6) is present within one hour. Once activated, NF-KB can induce the expression of several downstream targets that serve as important mediators of blood-brain-barrier (BBB) opening, leukocyte infiltration and secondary lesion expansion. Furthermore, our recent microarray data demonstrate an expansion of the inflammatory response during the first 24 hrs after ICH with elevated expression of additional cytokines, chemokines, inflammatory molecules and receptors. Specifically, we propose to define the temporal course, cellular location and treatment responses of early pro-inflammatory and target gene and protein expression in perihematomal brain tissue after ICH using molecular, biochemical, histological and immunocytochemical methods. Since clot removal in our porcine lobar ICH model markedly reduces edema and protects the BBB, we will determine if early surgery can interrupt inflammatory responses. We will employ anti-inflammatory drug therapies against NF-KB and pro-inflammatory cytokines that are supported by preliminary data demonstrating reduced edema and BBB protection with a cell permeable nuclear translocation inhibitor of activated NF-kB (SN5O), and roplipram, a phosphodiesterase-4 inhibitor that inhibits TNF-a synthesis. Lastly, since cytokine cascades are rapidly initiated after ICH, and early surgery is both logistically difficult and associated with an increased risk of rebleeding, we will determine whether combining acute anti-inflammatory drug therapy with delayed surgery is a clinically effective approach to treat ICH.
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