Inhibition of p38 mitogen-activated protein kinase provides neuroprotection in cerebral focal ischemia.
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.
SmithKline Beecham Pharmaceuticals, Department of Cardiovascular Pharmacology, King of Prussia, PA 19406, USA. Frank_C_Barone@SBPHRD.com
F C
FC
Barone
E A
EA
Irving
A M
AM
Ray
J C
JC
Lee
S
S
Kassis
S
S
Kumar
A M
AM
Badger
J J
JJ
Legos
J A
JA
Erhardt
E H
EH
Ohlstein
A J
AJ
Hunter
D C
DC
Harrison
K
K
Philpott
B R
BR
Smith
J L
JL
Adams
A A
AA
Parsons
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D007093:Imidazoles; D007375:Interleukin-1; D018696:Neuroprotective Agents; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C406525:SB 239063