Project V seeks to establish the mechanisms by which electrical stimulation of the cerebellar fastigial nucleus (FN) reduces the volume of the focal ischemic infarction produced by permanent occlusion of the middle cerebral artery (MCAO) in rat. Specifically, it tests the hypotheses that the central neurogenic protection results from interaction of two events: (a) a reduction in neuronal excitability, and (b) suppression of inflammatory reactions. Study I will determine whether (a) electrical stimulation of FN in anesthetized rats reduces the depolarizing (DC) waves generated in the ischemic penumbra after MCAO (b) FN stimulation in normal rats alters the threshold and pattern of spreading cortical depression; and (c) in case that excitability is altered, if the response can be attributed to alteration in neuronal Kplus channel function. Study II will examine whether (a) MCAO will induce, in brain, expression of the mRNAs and/or protein products for the pro-inflammatory molecules iNOS and lL1-beta; and the endothelial adhesion molecules ICAM and VCAM;(b) FN stimulation reduces the expression of these molecules by MCAO; (c) the inflammatory reactivity of vessels isolated from FN-stimulated brains is reduced compared to non-stimulated brains; (d) FN stimulation reduces the responses to lL-1 injection in brain; (e) FN stimulation modifies the transcription factor NFKbeta, which coordinates expression of inflammatory genes; (f) FN stimulation induces the mRNA and/or proteins for the anti-inflammatory cytokines lL4, lL10, lL-1Ra and/or TGFbeta.
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