Barone F C, Irving E A, Ray A M, Lee J C, Kassis S, Kumar S, Badger A M, Legos J J, Erhardt J A, Ohlstein E H, Hunter A J, Harrison D C, Philpott K, Smith B R, Adams J L, Parsons A A
SmithKline Beecham Pharmaceuticals, Department of Cardiovascular Pharmacology, King of Prussia, PA 19406, USA.
Med Res Rev. 2001 Mar;21(2):129-45. doi: 10.1002/1098-1128(200103)21:2<129::aid-med1003>3.0.co;2-h.
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.
丝裂原活化蛋白激酶（MAPKs）参与许多细胞过程。应激激活的MAPK，即p38，与细胞应激后的炎性细胞因子产生和细胞死亡有关。在此，我们证明了局灶性缺血性中风可诱导大脑中p38酶的激活（即磷酸化）。第二代p38 MAPK抑制剂SB 239063被鉴定具有更高的激酶选择性以及改善的细胞和体内活性，因此被选用于两种永久性局灶性缺血性中风大鼠模型的评估。SB 239063在中风前后口服给药，并在中风后静脉给药。血浆浓度水平超过了有效抑制p38活性的浓度。在中度和重度中风中，SB 239063均使梗死面积减少了28 - 41%，神经功能缺损减少了25 - 35%。此外，中风后降低p38活性的SB 239063的神经保护血浆浓度也降低了中风诱导的IL - 1β和TNFα的表达（即已知会导致中风诱导的脑损伤的细胞因子）。SB 239063还对培养的脑组织提供了对体外缺血的直接保护。这种强大的SB 239063诱导的神经保护作用强调了在缺血性中风损伤中靶向MAPK途径的重大机会，也表明应在其他神经系统损伤和神经退行性变的实验模型中评估p38抑制的保护作用。
