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Published on: February 16, 2011
Inhibition of p38 mitogen-activated protein kinase provides neuroprotection in cerebral focal ischemia
F C Barone1, E A Irving, A M Ray
1SmithKline Beecham Pharmaceuticals, Department of Cardiovascular Pharmacology, King of Prussia, PA 19406, USA. Frank_C_Barone@SBPHRD.com
Abstract:
Mitogen-activated protein kinases (MAPKs) are involved in many cellular processes. The stress-activated MAPK, p38, has been linked to inflammatory cytokine production and cell death following cellular stress. Here, we demonstrate focal ischemic stroke-induced p38 enzyme activation (i.e., phosphorylation) in the brain. The second generation p38 MAPK inhibitor SB 239063 was identified to exhibit increased kinase selectivity and improved cellular and in vivo activity profiles, and thus was selected for evaluation in two rat models of permanent focal ischemic stroke. SB 239063 was administered orally pre- and post-stroke and intravenously post-stroke. Plasma concentration levels were achieved in excess of those that effectively inhibit p38 activity. In both moderate and severe stroke, SB 239063 reduced infarct size by 28-41%, and neurological deficits by 25-35%. In addition, neuroprotective plasma concentrations of SB 239063 that reduced p38 activity following stroke also reduced the stroke-induced expression of IL-1beta and TNFalpha (i.e., cytokines known to contribute to stroke-induced brain injury). SB 239063 also provided direct protection of cultured brain tissue to in vitro ischemia. This robust SB 239063-induced neuroprotection emphasizes a significant opportunity for targeting MAPK pathways in ischemic stroke injury, and also suggests that p38 inhibition be evaluated for protective effects in other experimental models of nervous system injury and neurodegeneration.
Insights
Inhibiting the stress-activated p38 mitogen-activated protein kinase (MAPK) pathway with SB 239063 significantly reduced brain damage and neurological deficits in rat stroke models. This highlights p38 MAPK as a promising therapeutic target for ischemic stroke.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Mitogen-activated protein kinases (MAPKs) regulate cellular processes, with stress-activated p38 MAPK linked to inflammation and cell death.
- Focal ischemic stroke triggers p38 MAPK activation in the brain, suggesting its role in stroke pathology.
Purpose of the Study:
- To investigate the neuroprotective effects of the p38 MAPK inhibitor SB 239063 in rat models of focal ischemic stroke.
- To evaluate the impact of p38 MAPK inhibition on infarct size, neurological deficits, and inflammatory cytokine expression post-stroke.
Main Methods:
- SB 239063, a selective p38 MAPK inhibitor, was administered orally and intravenously in rat models of moderate and severe permanent focal ischemic stroke.
- Infarct volume, neurological deficits, and expression of IL-1beta and TNFalpha were assessed.
- Neuroprotection was also evaluated in cultured brain tissue subjected to in vitro ischemia.
Main Results:
- SB 239063 administration significantly reduced infarct size by 28-41% and neurological deficits by 25-35% in both stroke models.
- Effective plasma concentrations of SB 239063 reduced stroke-induced expression of inflammatory cytokines IL-1beta and TNFalpha.
- SB 239063 demonstrated direct neuroprotection in vitro against ischemia.
Conclusions:
- Targeting the p38 MAPK pathway with SB 239063 offers significant neuroprotection in experimental ischemic stroke.
- p38 MAPK inhibition is a promising therapeutic strategy for mitigating stroke-induced brain injury.
- Further evaluation of p38 inhibition in other nervous system injury models is warranted.
