This study was designed to investigate the effect of 002C-3, a derivative of magnolol, on transient cerebral middle occlusion （tMCAO） in a mice model and to identify the underlying mechanisms. 002C-3 （100 and 150 pg/kg, i.v. after ending occlusion） significantly reduced neurological deficit scores, infarct volumes, and brain water contents after 1.5 h MCAO and 24 h reperfusion. 002C-3 （75 150μg/kg） decreased the exudation of Evans blue from brain capillaries. 002C-3 （100 μg/kg） significantly inhibited the activity of MMP-9 and MMP-2 in the injured hemisphere. 002C-3 decreased the expression of autophagy-associated proteins, Beclin-1 and LC3B-Ⅱ, and increased the level of p62 in injured hemisphere. 002C-3 （100 pg/kg） significantly increased the expression of p-CaMKIV and p-HDAC4 in injured hemisphere. In conclusion, 002C-3 shows a neuroprotective effect on tMCAO injury in mice, and its mechanisms may be associated with alleviation of blood-brain barrier damage caused by the activation of MMPs, inhibition of autophagy, and stimulation of calcium signals related to cell survival. These findings suggest that 002C-3 is a neuroprotective agent that acts on multiple pathways.
Jingliang ZhangTao HuXiaoyan LiuYuanjun ZhuXiaoling ChenYe LiuYinye Wang
In the present study, we investigated anti-thrombotic effects of W007B, a water-soluble derivative of honokiol, with different models both in vitro and in vivo. Rat platelet aggregation was induced by adenosine diphosphate （ADP）, thrombin, arachidonic acid （AA） and collagen in vitro. The anti-thrombotic effects were evaluated with the arterio-venous shunt model, electrode-stimulated carotid thrombosis model in rats and ADP-induced acute pulmonary embolic model in mice. The bleeding time in vivo was examined with tail incision in mice. W007B inhibited ADP-, thrombin-, collagen- and AA-induced platelet aggregation in a concentration-dependent manner, with an ICs0 value of 899.5 μM, 212.9 μM, 266.0 μM and 52.5 μM, respectively. In vivo, W007B （2-10 mg/kg, ig） significantly reduced the thrombus weight in the model of arterio-venous shunt. Besides, W007B could effectively prolong the occlusion time in the electrode-stimulated carotid thrombosis model. Moreover, in the ADP-induced acute pulmonary embolism model in mice, 2.8-14 mg/kg of W007B significantly reduced the death of mice. In conclusion, W007B is effective on platelet aggregation, and it is most sensitive on AA-induced aggregation. W007B has potent anti-thrombotic effect on different arterial thrombosis models. It may be an orally active candidate of anti-thrombotic agents.
To explore the effect of multiple pathway intervention in acute cerebral ischemia injury, we prepared a medicine formula （formula 2） consisting of ginsenosides, pueraria flavonoids, ophiopogonis and borneol as a tool medicine. The effects of formula 2 and its components on PC12 cell viability and potential pathway were investigated, and the influence of this formula on venous thrombosis and platelet aggregation was also assessed, then the effect of formula 2 on middle cerebral artery occlusion （MCAO） reperfusion was observed in rats. Formula 2 markedly enhanced the cell viability, which was stronger than that of each individual component. Formula 2 significantly inhibited the NO production in PC12 cells induced by H202, and this effect was also stronger than that of each individual component. Moreover, formula 2 enhanced the SOD activity, and the effect was stronger than that of ginsenosides. In addition, formula 2 reduced the MDA content, and this effect was stronger than that of ophiopogonins. In vivo, formula 2 showed potent inhibitory effects on platelet aggregation and venous thrombosis. Furthermore, formula 2 （single dose, s.c.） significantly reduced the infarct volume and neurobehavioral scores in MCAO reperfusion rats. Take together, our results suggests that formula 2 has powerful ability of inhibiting the ischemia/reperfusion injury, and this effect might be attributed to its simultaneous intervention in the cascade reaction of neuronal injury via multiple pathways contributed by multiple components during cerebral ischemia/reperfusion.
