Role of p38 Mitogen-Activated Protein Kinase on Cerebral Vasospasm After Subarachnoid Hemorrhage

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Abstract
Background and Purpose— Inflammatory cytokines are involved in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). This study was conducted to examine the role of p38 mitogen-activated protein kinase (MAPK) in the development of vasospasm and cytokine production. Methods— We measured the expression levels of genes and proteins related to inflammation in human vascular smooth muscle cells (hVSMCs) treated with hemolysate and FR167653 (FR) (1μmol/L), a selective p38MAPK inhibitor, for 48 hours by TaqMan real-time reverse transcription-polymerase chain reaction (RT-PCR) and ELISA. Twenty-one dogs were assigned to 3 groups of 7 animals: control, placebo, and FR-treated (1 mg/kg/d) groups in a double-hemorrhage model. The effects were assessed through the caliber of the basilar artery, and the changes in gene expressions and the activation of p38MAPK were assessed by Western blot analysis. Results— Treatment of hVSMCs with hemolysate induced significant upregulation of interleukin (IL)-1α, IL-1β, and IL-8 gene and protein expressions, which was suppressed significantly with FR. The mean vessel caliber on day 7, as a percentage of that of day 0, was 49% in the placebo, and 74% in the FR group (P=0.0001). The gene expression levels of IL-1α, IL-1β, and IL-8 in the arterial wall were extremely elevated in the placebo, and significantly suppressed in the FR group (P=0.0027, 0.0002, and 0.0073). p38MAPK phosphorylation was stimulated in the placebo and hemolysate in vitro, and suppressed in the FR group. Conclusions— These results suggest that p38MAPK is activated in the arterial wall after SAH, leading to the development of vasospasm, possibly through the upregulation of inflammatory cytokines.

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