K-134, a Phosphodiesterase 3 Inhibitor, Prevents Brain Damage by Inhibiting Thrombus Formation in a Rat Cerebral Infarction Model

BackgroundK-134 is a more potent antiplatelet drug with a selective inhibitory effect on phosphodiesterase 3 (PDE3) compared with its analogue, cilostazol. ObjectivesThis study was performed to compare the ameliorating effects of K-134 and cilostazol on brain damage in an experimental photothrombotic cerebral infarction model. Methods and ResultsWe investigated the effects of oral preadministration of PDE3 inhibitors in a rat stroke model established by photothrombotic middle cerebral artery (MCA) occlusion. K-134 significantly prolonged MCA occlusion time at doses >10 mg/kg, and reduced cerebral infarct size at 30 mg/kg in the stroke model (n = 12, 87.5±5.6 vs. 126.8±7.5 mm3, Pin vitro. Also in an arteriovenous shunt thrombosis model, K-134 showed an antithrombotic effect greater than cilostazol. ConclusionsThese findings suggest that K-134, which has strong antithrombotic activity, is a promising drug for prevention of cerebral infarction associated with platelet hyperaggregability.

研究背景：K-134是一种抗血小板活性更强的药物，相较于其类似物西洛他唑（cilostazol），它对磷酸二酯酶3（phosphodiesterase 3，PDE3）具有选择性抑制作用。
研究目的：本研究旨在对比K-134与西洛他唑对实验性光血栓性脑梗死模型脑损伤的改善效果。
方法与结果：本研究探究了PDE3抑制剂口服预给药对光血栓法构建的大鼠大脑中动脉（middle cerebral artery，MCA）闭塞卒中模型的干预作用。在该卒中模型中，当给药剂量高于10 mg/kg时，K-134可显著延长大脑中动脉闭塞时长；当给药剂量为30 mg/kg时，K-134可缩小脑梗死体积（n=12，87.5±5.6 vs. 126.8±7.5 mm³，P<0.05）。体外实验中，K-134同样表现出优于西洛他唑的抗血小板聚集活性。此外，在动静脉分流血栓模型中，K-134的抗血栓作用也强于西洛他唑。
结论：上述研究结果表明，具备强抗血栓活性的K-134是预防血小板高聚集相关性脑梗死的极具潜力的候选药物。