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Experimental Models to Study the Neuroprotection of Acidic Postconditioning Against Cerebral Ischemia
Published on: July 31, 2017
Mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 deficiency protects brain from ischemic injury
Xinkang Wang1, Lin Xu, Hugh Wang
1Department of Cardiovascular Sciences, Bristol-Myers Squibb Company, Wilmington, Delaware 19880-0400, USA. xinkang.wang@bms.com
Abstract:
Mitogen-activated protein (MAP) kinase-activated protein kinase 2 (MK2) is one of several kinases directly regulated by p38 MAP kinase. A role of p38 MAP kinase in ischemic brain injury has been previously suggested by pharmacological means. In the present study, we provide evidence for a role of MK2 in cerebral ischemic injury using MK2-deficient (MK2(-/-)) mice. MK2(-/-) mice subjected to focal ischemia markedly reduced infarct size by 64 and 76% after transient and permanent ischemia, respectively, compared with wild-type mice. Furthermore, MK2(-/-) mice had significant reduction in neurological deficits. Real-time PCR analysis identified a significantly lower expression in interleukin-1beta mRNA (53% reduction) but not in tumor necrosis factor-alpha mRNA in MK2(-/-) mice over wild-type animals after ischemic injury. The significant reduction in interleukin-1beta was also confirmed in MK2(-/-) mice by enzyme-linked immunosorbent assay. The marked neuroprotection from ischemic brain injury in MK2(-/-) mice was not associated with the alteration of hemodynamic or systemic variables, activation of caspase-3, or apoptosis. Our data provide new evidence for the involvement of MAP kinase pathway in focal ischemic brain injury and suggest that this effect might be associated with the expression of interleukin-1beta in the ischemic brain tissue.
Insights
Mitogen-activated protein kinase-activated protein kinase 2 (MK2) deficiency significantly reduces ischemic brain injury and neurological deficits. This neuroprotection is linked to decreased interleukin-1beta expression, highlighting the MAP kinase pathway
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Mitogen-activated protein (MAP) kinase-activated protein kinase 2 (MK2) is regulated by p38 MAP kinase.
- p38 MAP kinase has been implicated in ischemic brain injury.
- The specific role of MK2 in cerebral ischemia remains to be elucidated.
Purpose of the Study:
- To investigate the role of MK2 in focal cerebral ischemic injury.
- To determine the impact of MK2 deficiency on infarct size and neurological outcomes.
- To explore the molecular mechanisms underlying MK2's involvement in ischemic brain injury.
Main Methods:
- Utilized MK2-deficient (MK2(-/-)) mice and wild-type littermates.
- Subjected mice to transient and permanent focal cerebral ischemia.
- Assessed infarct size, neurological deficits, interleukin-1beta and tumor necrosis factor-alpha mRNA expression, and apoptosis markers.
Main Results:
- MK2(-/-) mice exhibited significantly reduced infarct sizes (64-76%) compared to wild-type mice.
- Neurological deficits were significantly diminished in MK2(-/-) mice.
- Interleukin-1beta mRNA expression was markedly reduced (53%) in MK2(-/-) mice post-ischemia, a finding confirmed by ELISA.
- No significant changes were observed in tumor necrosis factor-alpha mRNA, caspase-3 activation, or apoptosis.
Conclusions:
- MK2 plays a crucial role in exacerbating ischemic brain injury.
- MK2 deficiency confers significant neuroprotection against focal cerebral ischemia.
- The neuroprotective effect of MK2 deficiency may be mediated, in part, by the downregulation of interleukin-1beta expression within the ischemic brain tissue.
