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Vol. 296, Issue 2, 312-321, February 2001
Cardiovascular Pharmacology (F.C.B., R.F.W., M.J.M., J.J.L.,
J.A.E., A.H.N., E.H.O., A.A.P.), Bone Biology (J.C.L., S.Ka., S.Ku.,
A.M.B.), Drug Metabolism (K.W., B.R.S.), and Medicinal Chemistry
(J.L.A.), SmithKline Beecham Pharmaceuticals, King of Prussia,
Pennsylvania; and Neuroscience Research, SmithKline Beecham
Pharmaceuticals, New Frontiers Science Park, Harlow, Essex, United
Kingdom (E.A.I., A.M.R., A.J.H., A.A.P.)
The stress-activated mitogen-activated protein kinase (MAPK) p38 has
been linked to the production of inflammatory
cytokines/mediators/inflammation and death/apoptosis following cell
stress. In these studies, a second-generation p38 MAPK inhibitor, SB
239063 (IC50 = 44 nM), was found to exhibit improved
kinase selectivity and increased cellular (3-fold) and in vivo (3- to
10-fold) activity over first-generation inhibitors. Oral SB 239063 inhibited lipopolysaccharide-induced plasma tumor necrosis
factor production (IC50 = 2.6 mg/kg) and reduced adjuvant-induced arthritis (51% at 10 mg/kg) in rats. SB
239063 reduced infarct volume (48%) and neurological deficits (42%)
when administered orally (15 mg/kg, b.i.d.) before moderate stroke.
Intravenous SB 239063 exhibited a clearance of 34 ml/min/kg, a volume
of distribution of 3 l/kg, and a plasma half-life of 75 min. An i.v.
dosing regimen that provided effective plasma concentrations of 0.38, 0.75, or 1.5 µg/ml (i.e., begun 15 min poststroke and continuing over
the initial 6-h p38 activation period) was used. Significant and
dose-proportional brain penetration of SB 239063 was demonstrated
during these infusion periods. In both moderate and severe stroke,
intravenous SB 239063 produced a maximum reduction of infarct size by
41 and 27% and neurological deficits by 35 and 33%, respectively. No
effects of the drug were observed on cerebral perfusion, hemodynamics,
or body temperature. Direct neuroprotective effects from oxygen and
glucose deprivation were also demonstrated in organotypic cultures of
rat brain tissue. This robust in vitro and in vivo SB 239063-induced
neuroprotection emphasizes the potential role of MAPK pathways in
ischemic stroke and also suggests that p38 inhibition warrants further
study, including protection in other models of nervous system injury and neurodegeneration.
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