Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, 720 Rutland Ave, Ross 347, Baltimore, MD 21205, USA.
Brain Res. 2012 Aug 30;1471:129-37. doi: 10.1016/j.brainres.2012.06.031. Epub 2012 Jul 20.
It is postulated that inhibition of cytosolic phospholipase A(2) alpha (cPLA(2)α) can reduce severity of stroke injury. This is supported by the finding that cPLA(2)α-deficient mice are partially protected from transient, focal cerebral ischemia. The object of this study was to determine the effect of cPLA(2)α inhibition with arachidonyl trifluoromethyl ketone (ATK) on stroke injury in mice. Male C57BL/6 mice were subjected to 1h of focal cerebral ischemia followed by 24 or 72 h of reperfusion. Mice were treated with ATK or vehicle by intermittent intraperitoneal injection or continuous infusion via an implanted infusion pump. ATK injections 1h before and then 1 and 6h after the start of reperfusion significantly reduced infarction volumes in striatum and hemisphere after 24h of reperfusion. ATK did not reduce injury if it was not administered before onset of ischemia or was not administered after 6h of reperfusion. Intermittent doses of ATK failed to reduce infarct volume after 72 h of reperfusion. Continuous infusion with ATK throughout 72h of reperfusion significantly reduced cortical and whole hemispheric infarct volume compared to vehicle treatment. Following ischemia and reperfusion, ATK treatment significantly reduced brain PLA(2) activity. These results are the first to demonstrate a therapeutic effect of cPLA(2)α inhibition on ischemia and reperfusion injury and define a therapeutic time window. cPLA(2)α activity augments injury in the acute and delayed phases of cerebral ischemia and reperfusion injury. We conclude that cPLA(2)α inhibition may be clinically useful if started before initiation of cerebral ischemia.
据推测，抑制细胞质型磷脂酶 A（2）α（cPLA（2）α）可以减轻中风损伤的严重程度。这一发现得到了支持，即 cPLA（2）α 缺陷小鼠在短暂性、局灶性脑缺血中得到部分保护。本研究的目的是确定用花生四烯酸三氟甲基酮（ATK）抑制 cPLA（2）α 对小鼠中风损伤的影响。雄性 C57BL/6 小鼠接受 1 小时局灶性脑缺血，然后再进行 24 或 72 小时再灌注。通过间歇性腹腔内注射或通过植入的输注泵进行连续输注，用 ATK 或载体处理小鼠。在再灌注开始前 1 小时和再灌注开始后 1 小时和 6 小时给予 ATK 注射，可显著减少再灌注 24 小时后的纹状体和半球梗死体积。如果在缺血发作前未给予 ATK 或在再灌注 6 小时后未给予 ATK，则不会减少损伤。再灌注 72 小时后，间歇性 ATK 剂量未能减少梗死体积。在 72 小时的再灌注期间用 ATK 连续输注可显著减少皮质和整个半球的梗死体积，与载体处理相比。缺血再灌注后，ATK 处理可显著降低脑 PLA（2）活性。这些结果是首次证明 cPLA（2）α 抑制对缺血再灌注损伤的治疗作用，并定义了治疗时间窗。cPLA（2）α 活性在脑缺血和再灌注损伤的急性和迟发性阶段增加损伤。我们得出结论，如果在脑缺血开始前开始，cPLA（2）α 抑制可能具有临床意义。
