Switching Off Vascular MAPK Signaling: A Novel Strategy to Prevent Delayed Cerebral Ischemia Following Subarachnoid Hemorrhage

Abstract

Patients who initially survive the rupture and repair of a brain aneurysm often take a devastating turn for the worse some days later and die or suffer permanent neurologic deficits. This catastrophic sequela is attributed to a delayed phase of global cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH), but we lack effective treatment. Here we present our view, based on 20 years of research, that the initial drop in blood flow at the time of rupture triggers genomic responses throughout the brain vasculature that manifest days later as increased vasoconstriction and decreased cerebral blood flow. We propose a novel treatment strategy to prevent DCI by early inhibition of the vascular mitogen-activated protein kinase (MAPK) pathway that triggers expression of vasoconstrictor and inflammatory mediators. We summarize evidence from experimental SAH models showing early treatment with MAPK inhibitors "switches off" these detrimental responses, maintains flow, and improves neurological outcome. This promising therapy is currently being evaluated in clinical trials.

Keywords: Cerebral vasculature; Delayed cerebral ischemia; MAPK kinase inhibitor; Subarachnoid hemorrhage; Vasoconstriction.

Fig. 1

Vascular changes in response to SAH. Schematic illustration of the time course of events following SAH with particular emphasis on the evolving response of vascular smooth muscle in cerebral arteries and microvessels as described in the text. Abbreviations: SAH subarachnoid hemorrhage, VSM vascular smooth muscle, FAK focal adhesion kinase, MEK mitogen-activated protein kinase kinase, ERK1/2 extracellular signal-related kinase, TF transcription factor, MMP matrix metalloproteinase, BBB blood–brain barrier, DCI delayed cerebral ischemia

Fig. 2

Effect of raf, MEK1/2, and ERK1/2 inhibitors in experimental SAH. Rationale for the proposed novel therapy to prevent DCI following SAH based on studies in experimental animal models