Signaling Pathways for Early Brain Injury after Subarachnoid Hemorrhage

Abstract

Few studies have examined the signaling pathways that contribute to early brain injury after subarachnoid hemorrhage (SAH). Using a rat SAH model, the authors explored the role of vascular endothelial growth factor (VEGF) and mitogen-activation protein kinase (MAPK) in early brain injury. Male Sprague-Dawley rats (n = 172) weighing 300 to 350 g were used for the experimental SAH model, which was induced by puncturing the bifurcation of the left anterior cerebral and middle cerebral arteries. The blood-brain barrier (BBB), brain edema, intracranial pressure, and mortality were evaluated at 24 hours after SAH. The phosphorylation of VEGF and different MAPK subgroups (ERK1/2, p38, and JNK) were examined in both the cortex and the major cerebral arteries. Experimental SAH increased intracranial pressure, BBB permeability, and brain edema and produced high mortality. SAH induced phosphorylation of VEGF and MAPKs in the cerebral arteries and, to a lesser degree, in the cortex. PP1, an Src-family kinase inhibitor, reduced BBB permeability, brain edema, and mortality and decreased the phosphorylation of VEGF and MAPKs. The authors conclude that VEGF contributes to early brain injury after SAH by enhancing the activation of the MAPK pathways, and that the inhibition of these pathways might offer new treatment strategies for SAH.

Cerebrospinal fluid high mobility group box 1 is associated with neuronal death in subarachnoid hemorrhage

“…However, the mechanisms that induce the cell death after SAH are still undefined, though inflammation, such as via the MAPKs pathway, has been mentioned as one of the critical mediators. [27][28][29] There is growing evidence that HMGB1 and RAGE signaling and related inflammatory reactions are involved in the pathogenesis of various disorders, including cardiovascular, neurodegenerative, and immune disorders. 12,20,[30][31][32][33] We have recently established that plasma levels of HMGB1 as well as interactions between HMGB1 and RAGE were increased significantly after ischemic stroke onset both in human and mice.…”

Subtype Activation and Interaction of Protein Kinase C and Mitogen-Activated Protein Kinase Controlling Receptor Expression in Cerebral Arteries and Microvessels After Subarachnoid Hemorrhage

“…Several other studies have reported increased activity of all 3 groups of MAPK in cerebral arteries after SAH, but none has examined the time course. 36 It is therefore important to unravel the temporal changes and sequential activation of MAPK. In addition, the event is associated not only with the basal circle of Willis activation (with the blood deposition), but also with the intracerebral microvessels, which may shed more light on the reasons behind the general regional CBF reduction 13,22 and the ischemia which, in people, sometimes is observed despite no angiographic vasospasm.…”

Neuroprotection against surgically induced brain injury

“…Src tyrosine kinase and the ubiquitous MAPKs are well implicated in brain injury resulting from different causes such as cerebral ischemia, trauma and hemorrhage [2,21,22,24,26,27,31,32,45] and have an important role in cerebral edema [26,31]. Inhibition of src tyrosine kinase with PP1 reduces the expression of vascular endothelial growth factor (VEGF), protects blood-brain barrier, and reduces brain edema immediately after subarachnoid hemorrhage [26] and also offers cerebral protection against stroke by influencing the VEGFmediated vascular permeability and cerebral edema [33]. In this animal model, we have observed a marked effect of PP1 on brain edema as shown in Figure 2.…”