SB 239063, a second-generation p38 mitogen-activated protein kinase inhibitor, reduces brain injury and neurological deficits in cerebral focal ischemia

The stress-activated mitogen-activated protein kinase (MAPK) p38 has been l inked to the production of inflammatory cytokines/mediators/inflammation an d death/apoptosis following cell stress. In these studies, a second-generat ion p38 MAPK inhibitor, SB 239063 (IC50 = 44 nM), was found to exhibit impr oved kinase selectivity and increased cellular (3-fold) and in vivo (3- to 10-fold) activity over first-generation inhibitors. Oral SB 239063 inhibite d lipopolysaccharide-induced plasma tumor necrosis factor production (IC50 = 2.6 mg/kg) and reduced adjuvant-induced arthritis (51% at 10 mg/kg) in ra ts. SB 239063 reduced infarct volume (48%) and neurological deficits (42%) when administered orally (15 mg/kg, b.i.d.) before moderate stroke. Intrave nous SB 239063 exhibited a clearance of 34 ml/min/kg, a volume of distribut ion of 3 l/kg, and a plasma half-life of 75 min. An i.v. dosing regimen tha t provided effective plasma concentrations of 0.38, 0.75, or 1.5 mug/ml (i. e., begun 15 min poststroke and continuing over the initial 6-h p38 activat ion period) was used. Significant and dose-proportional brain penetration o f SB 239063 was demonstrated during these infusion periods. In both moderat e and severe stroke, intravenous SB 239063 produced a maximum reduction of infarct size by 41 and 27% and neurological deficits by 35 and 33%, respect ively. No effects of the drug were observed on cerebral perfusion, hemodyna mics, or body temperature. Direct neuroprotective effects from oxygen and g lucose deprivation were also demonstrated in organotypic cultures of rat br ain tissue. This robust in vitro and in vivo SB 239063-induced neuroprotect ion emphasizes the potential role of MAPK pathways in ischemic stroke and a lso suggests that p38 inhibition warrants further study, including protecti on in other models of nervous system injury and neurodegeneration.