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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS030652-08A1
Application #
6548175
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Jacobs, Tom P
Project Start
2002-07-01
Project End
2006-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
8
Fiscal Year
2002
Total Cost
$299,250
Indirect Cost
Name
University of Cincinnati
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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Lu, Aigang; Clark, Joseph F; Broderick, Joseph P et al. (2008) Reperfusion activates metalloproteinases that contribute to neurovascular injury. Exp Neurol 210:549-59
Loftspring, Matthew C; Clark, Joseph F; Wagner, Kenneth R (2007) A novel duplex ELISA method for quantitation of plasma proteins in areas of brain edema. Brain Res 1162:130-2
Wagner, Kenneth R (2007) Modeling intracerebral hemorrhage: glutamate, nuclear factor-kappa B signaling and cytokines. Stroke 38:753-8
Loftspring, Matthew C; Beiler, Shauna; Beiler, Christian et al. (2006) Plasma proteins in edematous white matter after intracerebral hemorrhage confound immunoblots: an ELISA to quantify contamination. J Neurotrauma 23:1904-11
Wagner, K R; Beiler, S; Beiler, C et al. (2006) Delayed profound local brain hypothermia markedly reduces interleukin-1beta gene expression and vasogenic edema development in a porcine model of intracerebral hemorrhage. Acta Neurochir Suppl 96:177-82
Wagner, Kenneth R; Dean, Christopher; Beiler, Shauna et al. (2005) Plasma infusions into porcine cerebral white matter induce early edema, oxidative stress, pro-inflammatory cytokine gene expression and DNA fragmentation: implications for white matter injury with increased blood-brain-barrier permeability. Curr Neurovasc Res 2:149-55
Wagner, Kenneth R; Zuccarello, Mario (2005) Local brain hypothermia for neuroprotection in stroke treatment and aneurysm repair. Neurol Res 27:238-45
Wagner, Kenneth R; Jauch, Edward C (2004) Extending the window for acute stroke treatment: thrombolytics plus CNS protective therapies. Exp Neurol 188:195-9

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