Early MEK1/2 inhibition after global cerebral ischemia in rats reduces brain damage and improves outcome by preventing delayed vasoconstrictor receptor upregulation.

BACKGROUND: Global cerebral ischemia following cardiac arrest is associated with increased cerebral vasoconstriction and decreased cerebral blood flow, contributing to delayed neuronal cell death and neurological detriments in affected patients. We hypothesize that upregulation of contractile ETB and 5-HT1B receptors, previously demonstrated in cerebral arteries after experimental global ischemia, are a key mechanism behind insufficient perfusion of the post-ischemic brain, proposing blockade of this receptor upregulation as a novel target for prevention of cerebral hypoperfusion and delayed neuronal cell death after global cerebral ischemia. The aim was to characterize the time-course of receptor upregulation and associated neuronal damage after global ischemia and investigate whether treatment with the MEK1/2 inhibitor U0126 can prevent cerebrovascular receptor upregulation and thereby improve functional outcome after global cerebral ischemia. Incomplete global cerebral ischemia was induced in Wistar rats and the time-course of enhanced contractile responses and the effect of U0126 in cerebral arteries were studied by wire myography and the neuronal cell death by TUNEL. The expression of ETB and 5-HT1B receptors was determined by immunofluorescence. RESULTS: Enhanced vasoconstriction peaked in fore- and midbrain arteries 3 days after ischemia. Neuronal cell death appeared initially in the hippocampus 3 days after ischemia and gradually increased until 7 days post-ischemia. Treatment with U0126 normalised cerebrovascular ETB and 5-HT1B receptor expression and contractile function, reduced hippocampal cell death and improved survival rate compared to vehicle treated animals. CONCLUSIONS: Excessive cerebrovascular expression of contractile ETB and 5-HT1B receptors is a delayed response to global cerebral ischemia peaking 3 days after the insult, which likely contributes to the development of delayed neuronal damage. The enhanced cerebrovascular contractility can be prevented by treatment with the MEK1/2 inhibitor U0126, diminishes neuronal damage and improves survival rate, suggesting MEK1/2 inhibition as a novel strategy for early treatment of neurological consequences following global cerebral ischemia.

Plasticity of cerebrovascular smooth muscle cells after subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is most often followed by a delayed phase of cerebral ischemia which is associated with high morbidity and mortality rates. The causes underlying this delayed phase are still unsettled, but are believed to include cerebral vasospasm, cortical spreading depression, inflammatory reactions, and microthrombosis. Additionally, a large body of evidence indicates that vascular plasticity plays an important role in SAH pathophysiology, and this review aims to summarize our current knowledge on the phenotypic changes of vascular smooth muscle cells of the cerebral vasculature following SAH. In light of the emerging view that the whole cerebral vasculature and the cells of the brain parenchyma should be viewed as one integrated neurovascular network, phenotypical changes are discussed both for the cerebral arteries and the microvasculature. Furthermore, the intracellular signaling involved in the vascular plasticity is discussed with a focus on the Raf-MEK1/2-ERK1/2 pathway which seems to play a crucial role in SAH pathology.