Key result
PKC or raf inhibitors prevent SAH-induced MAPK and PKC activation in rat cerebral vessels.
Why the study?
The pathogenesis of cerebral ischemia associated with subarachnoid hemorrhage remains elusive, particularly regarding MAPK and PKC subtype activation in cerebral vessels.
Specific subtypes of the MAPK and PKC pathways are activated in cerebral arteries after SAH, and this activation can be prevented by targeted kinase inhibitors in a rat model.
PKC/raf inhibitors prevent SAH-induced kinase activation in rat cerebral vessels; leaves open translation to prevent human cerebral ischemia.
BACKGROUND AND PURPOSE: The pathogenesis of cerebral ischemia associated with subarachnoid hemorrhage (SAH) still remains elusive. The aim of this study was to examine the involvement of mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) subtypes in the pathophysiology of cerebral ischemia after SAH in cerebral arteries and microvessels and to examine temporal activation of the kinases. We hypothesize that treatment with a MAPK or PKC inhibitor will prevent the SAH-induced kinase activation in brain vessels. METHODS: SAH was induced by injecting 250 microL blood into the prechiasmatic cistern in the rat. The activation of different MAPK and PKC isotypes in large circle of Willis cerebral arteries and intracerebral microvessels was examined at 0, 1, 3, 6, 12, 24, and 48 hours after SAH and after intrathecal treatment with PKC or MAPK inhibitor by use of Western blot. RESULTS: Among the 8 investigated PKC isoforms, only PKC delta was activated at 1 hour and at 48 hours, whereas PKC alpha was activated at 48 hours after SAH. For the MAPKs, there was early phosphorylation at 1 hour of extracellular signal-regulated kinase 1/2, whereas c-jun N-terminal kinase and p38 showed enhanced phosphorylation only at 48 hours after SAH. The pattern was identical in large cerebral arteries and in intracerebral microvessels. Treatment with either the PKC (RO-31-7549) or the raf (SB386023-b) inhibitor prevented the kinase activation. CONCLUSIONS: The results show that specific subtypes of the MAPK and PKC pathways are activated in cerebral arteries after SAH and the PKC and raf inhibitors are able to prevent this activation.
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Ansar et al. (2007) studied Subarachnoid hemorrhage (SAH). PKC inhibitor (RO-31-7549) or raf inhibitor (SB386023-b) was evaluated on Activation of MAPK and PKC isotypes in cerebral arteries and intracerebral microvessels. Treatment with PKC (RO-31-7549) or raf (SB386023-b) inhibitors prevented the SAH-induced activation of specific MAPK and PKC subtypes in rat cerebral arteries and microvessels.
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