Inflammatory Mechanisms in Cerebral Ischemia

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At the experimental level, hypothermia has consistently been an effective means of reducing cerebral ischemic injury. Although the mechanisms underlying this neuroprotection have been attributed to the preservation of metabolic stores and reducing excitatory amino acid release, this cannot explain the equally robust protection seen with only small decreases in brain temperature, or when brain cooling is delayed by a few hours. Recent work in the area of stroke has also shown that inflammatory processes are activated and exacerbate injury by the release of reactive oxygen species (ROS), proteases, and lipases leading to increases in cerebral edema and local tissue destruction. Inflammatory stimuli upregulate inflammatory cytokines, which activate microglia and stimulate expression of adhesion molecules. These latter proteins are involved in attracting leukocytes to activated and damaged endothelium, which then enter damaged tissue. We, and a few other groups have found that inhibition of neutrophil migration reduces ischemic injury following experimental stroke, and that mild hyopthermia attenuates neutrophil infiltration into ischemic brain regions. We purpose to further explore the mechanisms known to mediate this inflammatory response, and determine whether mild hypothermia alters them. Using models of brain ischemia and inflammation, we will first test the hypothesis that mild hypothermia attenuates cerebral infiltration of leukocyte subpopulations, and suppresses microglial activation. We will then study whether mild hypothermia alters expression of inflammatory mediators such as the inflammatory cytokines IL- 1beta (interleukin-1beta) and TNF-alpha (tumor necrosis factor- alpha), and adhesion molecules. We will then determine whether mild hypothermia attenuates inflammatory cell generation of potentially toxic substances such as ROS, inducible nitric oxide synthase (iNOS), and excitatory amino acids. To further confirm the temperature dependence of inflammation and its effects on brain injury, we will determine whether mice deficient in ICAM-1 are protected against hyperthermia. The results of this study should provide insight into the protective role of hypothermia, and may suggest anti-inflammatory targets for stroke treatment.