| Laetispicine is extracted and isolated from Piper laetispicum C.DC by our research group, its significant antidepressant activity has been proved by results of pharmacological studies, moreover it also possess antinociceptive and anxiolytic effects.The result of experiments suggested that the antidepression mechanism of laetispicine was not the same to other antidepressants, so it may be a new type antidepressant.In this article, the pharmacokinetics characteristics of laetispicine and its preliminary studies on antidepressant mechanism were evaluated.1.Pharmacokinetics study of laetispicine.Pharmacokinetics characteristics of laetispicine were studied after intravenous (2.5mg/kg) and oral administration(10mg/kg,20mg/kg,50mg/kg) in rats, and absolute oral bioavailability was calculated. The tissue distribution of laetispicine was investigated after oral administration (20mg/kg) in rats. The Caco-2 cell model was used to study the transport characteristics of laetispicine. The affects of pH, temperature, concentration and P-gp to laetispicine were investigated, and then the absorption of laetispicine in small intestine was evaluated. The metabolism of laetispicine in liver microsome in vitro was investigated. Besides, the metabolites in feces and urine of rat administrated with laetispicine were detected.Results:The Tmax, T1/2,bioavailability of laetispcine in rats was 3h,7.82±1.58h, and 23.12±4.96% respectively. Stomach, liver, intestine were organ laetispicine distributed in, and the ratio of AUCbrain/AUCplasm was 0.949.The absorptive transport of laetispicine was pH dependent and the transport was enhanced at pH8 comparing acidic pH on the apical side. The transport of laetispicine was negatively correlated to concentration, inhibited by low temperature, and enhanced by adding the inhibitors of P-gp. It is supposed that there may be some carrier without direction and interacting with P-gp protein participat the transport of laetispicine in Caco-2 cell.The Papp of laetispicine is(5.6±1.04)×10-6cm/sec, which proved that laetispicine is hard to be absorbed. Metabolite M supposed to be one of metabolites of laetispcine metabolized by CYP2C9 in liver.Conclusion:Laetispicine could easily cross blood brain barrier in rats. The relatively lower bioavailability may be due to low absorption.2.The antidepressant mechanism preliminary study of laetispicine.The antidepressant activity of 31 analogues with laetispicine was screened by force swimming test, and its structure-activity relationship was discussed. The protection of laetispicine on PC 12 cells against glutamate induced injury was investigated and the mechanism was discussed as well.Results:The isolated double bonds, conjugated double bonds on the carbon-chain and the isobutyl of laetispicine structure was necessary to antidepressant activity, the substituent group of benzene ring was related to activity, but the methylenedioxy group was not the necessary structure.PC12 cells injured by 20mM glutamate could be protected by laetispcine, especially concentration of laetispicine was 0.5?M (P<0.05).Laetispicine could enhance the viability of PC 12 cells injured by glutamate, reduce the leakage of LDH, up-regulating Bcl-2 protein expression, and inhibiting Bad protein expression.Conclusion:Laetispicine could protect PC12 cells injured by glutamate, and its mechanism might be regulating expression of relative apoptosis protein.The absorption, distribution, metabolism, excretion of laetispicine were investigsted. The antidepressant mechanism of laetispicine was preliminarily studied by discussing the structure-activity relationship and investigating the protection of leatispicine on PC 12 cells injured by glutamate.The researches are very important to the new drug development and clinical application of laetispicne. |
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