Treatment with ERK1/2 inhibitor 6 h post SAH prevent the cerebrovascular receptor upregulation

Abstract

Objective: Our hypothesis suggests that cerebral ischemia leads to pathophysiological receptor changes in the vascular smooth muscle cells via activation of extracellular signal-regulated kinase ERK1/2. Presently we wanted to find out the therapeutic window for an ERK1/2 inhibitor and thereby investigate its clinical relevance. Methods: SAH was induced by injecting 250 μl blood into the prechiasmatic cistern. Six, 12 and 24 h after the induced SAH the ERK1/2 inhibitor SB-386023-b was injected intracisternally. Two days after the SAH the cerebral arteries were harvested and contractile responses to endothelin-1 (ET-1) and 5-carboxamidotryptamine (5-CT) were investigated in myographs. In addition, the mRNA and protein levels of ET and 5-HT1 receptors were investigated by real time PCR and immunohistochemistry. Results: Treatment with the ERK1/2 inhibitor SB-386023-b at 6 h after the SAH decreased the elevated maximum contraction elicited by application of ET-1 and 5-CT in cerebral arteries considerably compared to SAH. The ERK1/2 inhibition prevented the upregulated ETB and 5-HT1B receptor mRNA and protein levels seen after SAH. Conclusion Since treatment with the ERK1/2 inhibitor 6 h after SAH abolished the SAH induced effects, it is of high clinical relevance and may be an important approach towards new stroke therapies in man. The study was supported by the Swedish Heart-Lung Foundation and the Lundbeck Foundation.