Zhiqiang Shen

Antiplatelet aggregation activity of diterpene alkaloids from Spiraea japonica

Six diterpene alkaloids with an atisine-type C(20)-skeleton isolated from the Chinese herbal medicines Spiraea japonica var. acuta and S. japonica var. ovalifolia, as well as eight derivatives of spiramine C and spiradine F were evaluated for the ability to inhibit aggregation of rabbit platelets induced by arachidonic acid, ADP, and platelet-activating factor (PAF) in vitro. The results showed that 12 of the 14 atisine-type diterpene alkaloids significantly inhibited PAF-induced platelet aggregation in a concentration-dependent manner, but had no effect on ADP- or arachidonic acid-induced aggregation, exhibiting a selective inhibition. It is the first report that C(20)-diterpene alkaloids inhibit PAF-induced platelet aggregation. However, spiramine C1 concentration-dependently inhibited platelet aggregation induced by PAF, ADP and arachidonic acid with IC(50) values of 30.5+/-2.7, 56.8+/-8.4 and 29.9+/-9.9 microM, respectively, suggesting a non-selective antiplatelet aggregation action. The inhibitory effect of spiramine C1 on arachidonic acid was as potent as that of aspirin. Primary studies of the structure-activity relationships for inhibition of PAF-induced aggregation showed that the oxygen substitution at the C-15 position and the presence of an oxazolidine ring in spiramine alkaloids were essential to their antiplatelet aggregation effects. These results suggest that the atisine-type alkaloids isolated from S. japonica are a class of novel antiplatelet aggregation agents.

Cerebroprotective Effects of Dimeric Copper(II)Bis(o-acetoxybenzoate) on Ischemia-reperfusion Injury in Gerbils

The cerebroprotective effects of copper aspirinate [dimeric copper(II) bis(o-acetoxybenzoate)] were investigated in gerbils subjected to 10-min global cerebral ischemia followed b 60-min reperfusion. The results showed that intragastric copper aspirinate (7.5, 15.0 and 30.0 mg Kg−1) markedly promoted the recovery of the electroencephalogram amplitude, attenuated the increase of lipid peroxide content and the decrease of superoxide dismutase activity in the cortex during ischemia-reperfusion injury. It suggested that copper aspirinate possesses potential neuroprotective properties, the mechanism of which might be related to an increase of the activity of endogenous superoxide dismutase.

Inhibitory Effects of Dimeric Copper(II) bis(o-acetoxybenzoate) on Platelet-neutrophil adhesion and Thrombosis

Antithrombotic effect of the copper-aspirin complex (dimeric copper(II) bis(o-acetoxybenzoate) was evaluated in the model of venous thrombosis; its effects on platelet-neutrophil adhesion were investigated by use of rosette assay. The results showed that the intragastrically administered copper-aspirin complex (5, 7, and 10 mg kg-1) dose-dependently lowered the wet and dry thrombus weight; it significantly decreased the binding of arachidonic acid-activated platelets to neutrophils with an IC50 value of 41.5 μmol L-1. The results suggested that copper aspirinate inhibited platelet-neutrophil adhesion and resulted in a more potent antithrombotic activity.

Potential application of copper aspirinate in preventing and treating thromboembolic diseases.

The efficacy of copper aspirinate against thrombotic diseases has been tested in animal models. The results show that copper aspirinate, following ig pretreatment for 7 days at 0.012mmol/kg markedly prolonged the bleeding time and inhibited the mortality induced by arachidonic acid (AA) in mice. On cereral ischemia model pretreatment with 0.018mmol/kg copper aspirinate ig significantly increased survival of animals and the density of intact hippocampal CA1 cells and decreased brain calcium concentration. Its anticerebral ischemia activity was superior to or equal to nimodipine. It is, therefore, suggested that copper aspirinate is very promising in becoming an antithrombotic drug in preventing and treating thrombotic diseases.

Antitumor Activity of the Carboplatin-α-Cyclodextrin Adduct

Antitumor activity of the adduct between Carboplatin and α-cyclodextrin has been tested against Sarcoma 180 (S180) and Ehrlich ascites carcinoma (EAC) murine tumors. The preliminary toxicity has also been evaluated by histological examinations of the treated animals. The results show the adduct has less antitumor efficacy than and similar toxicity to Carboplatin.