Cerebral ischemia occurs when the arterial blood supply to the brain is obstructed, resulting in areas of brain damage or infarcts. The resulting ischemic brain injury is accompanied by the increased synthesis of inflammatory molecules, cytokines and reactive oxygen species in neurons, glia and in the cerebral vasculature. Both ischemia and the induced cytokines upregulate the expression of downstream proinflammatory molecules. The pro-inflammatory response to ischemic brain injury is associated with increased infarct size and poor neurological prognosis; therefore compounds that block inflammation are potentially useful as therapies to treat cerebral ischemia. Neuregulin is a pleitrophic growth factor structurally related to epidermal growth factor (EGF). Neuregulin transcripts have been detected in neurons and cerebral blood vessels while its receptors (erbBs) are expressed primarily in neurons in the cerebral cortex, hippocampus, cerebellum and cholinergic nuclei. Preliminary data from our laboratory demonstrate that neuregulin inhibits cytokine-induced gene expression in cultures of cortical and hippocampal neurons. Several recent reports have implicated a role for neuregulin in the protection of neurons against brain injury. Neuregulin decreased inflammation, pro-inflammatory gene expression and demyelination in a mouse model of experimental autoimmune encephalomyelitis (EAE). Neuregulin and its receptors were shown to be upregulated in experimental models of traumatic and mechanical brain injury. In each case, the induction of neuregulin and erbBs was localized to cells at the edge of the lesion (penumbra) suggesting a role for neuregulin and erbBs in neural protection and repair. A specific role for neuregulin in ischemic brain injury has not been elucidated. Therefore, we will examine the potential neuroprotective effect of neuregulin and erbB receptor induction in a rodent model of brain ischemia using the following aims: (1) Investigate the expression of neuregulin or erbB receptors ischemic brain injury using a rat middle cerebral artery occlusion (MCAO) model, (2) To examine the expression of neuregulin and its receptors by rat neuronal cells in culture following exposure to hypoxia and (3) Investigate the effects of neuregulin on baseline, hypoxia and cytokine-induced inflammatory gene in rat neuronal cultures and examine neuroprotective effects of neuregulin on cortical cells. These studies will increase our understanding of neuregulin and potentially lead to development of new therapies that will improve clinical outcomes among patients who are treated for acute stoke.
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