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Antithrombotic therapy has become an important goal for the treatment of ischemic disorders such as cerebral ischemia. Our recent studies found that Z-ligustilide (LIG), a characterized 3-n-alkylphthalide constituent of Radix Angelica sinensis essential oil, exerted significant neuroprotection against cerebral ischemic damage in several animal models. The present study evaluated the antithrombotic activity of LIG and its effect on platelet aggregation and coagulation time. LIG (10 or 40 mg/kg) was intragastrically administered to rats once daily for 3 days. Our results showed that LIG significantly and dose-dependently reduced arterial thrombus weight in an arteriovenous shunt thrombosis in rats and platelet aggregation induced by adenosine diphosphate in rats ex vivo. Meanwhile, LIG at 10 or 40 mg/kg had no significant effect on coagulation time, including activated partial thromboplastin time and prothrombin time, in rats ex vivo. The present study demonstrated for the first time that LIG may exert efficient antithrombotic activity through inhibition of platelet aggregation, without effecting coagulation time of peripheral blood. These data, together with the previously reported neuroprotective effects of LIG on cerebral ischemia, suggest that the antithrombotic activity of LIG may contribute to its potential for the treatment of ischemic diseases, including ischemic stroke.

Z-ligustilide (Z-LIG) is the primary lipophilic compound of the Chinese medicine Danggui (Radix Angelica sinensis). Previous studies demonstrated that Z-LIG had significant neuroprotective potential in both transient and permanent cerebral ischemia, possibly through antioxidant and anti-apoptotic mechanisms. The present study examined the mechanisms of Z-LIG on hydrogen peroxide (H(2)O(2))-induced injury in PC12 cells. Following exposure of the cells to H(2)O(2 )(500 microM), a significant reduction in cell survival and total antioxidant capacity (TAC), as well as increased intracellular reactive oxygen species (ROS), were observed. In addition, H(2)O(2 )treatment significantly upregulated Bax expression, cleaved-caspase 3, and cytosolic cytochrome-c, and decreased Bcl-2 protein levels. Pretreatment of the cells with Z-LIG (0.1, 1.0, 2.5, or 5.0 microg/ml) significantly attenuated H(2)O(2)-induced cell death, attenuated increased intracellular ROS levels, and decreased Bax expression, cleaved-caspase 3, and cytochrome-c. Further, Z-LIG improved cellular TAC and concentration-dependently upregulated Bcl-2 expression. These results demonstrate that Z-LIG has a pronounced protective effect against H(2)O(2)-induced cytotoxicity, at least partly through improving cellular antioxidant defense and inhibiting the mitochondrial apoptotic pathway. These findings suggest that Z-LIG may be useful in the treatment of neurodegenerative disorders in which oxidative stress and apoptosis are mainly implicated.

The present study investigated the effect of Z-Ligustilide (LIG), a characterized 3-n-alkyphthalide derivative existed in many medical Umbelliferae plants, on permanent focal ischemic brain injury in rats. Focal cerebral ischemia was induced by the occlusion of middle cerebral artery (MCA) for 24 h. LIG (20, or 80 mg/kg), orally administered at 2 h after ischemia, reduced the cerebral infarct volumes by 48.29% and 84.87% respectively compared to control group as visualized by 2,3,5-triphenyltetrazolium chloride (TTC) staining (p<0.01). Treatment with LIG could dose-dependently reduce brain swelling by 68.62% and 82.08% (p<0.01), and significantly improve behavioral deficits (p<0.01). In addition, LIG at the above used doses had no significant effect on rat body temperature. These data, along with previous findings in our lab demonstrating the neuroprotective effects of LIG in transient cerebral ischemia, suggest that LIG may be a potential neuroprotective agent for the treatment of ischemic stroke in future.