葡萄内酯在小鼠体内的药代动力学特征及其对CUMS抑郁模型的作用与机制OA

Objective:To systematically explore the pharmacokinetic distribution characteristics of the natural coumarin compound Auraptene in mice,as well as its improving effects and molecular mechanism on depression-like behavior induced by chronic unpredictable mild stress(CUMS).Methods:Male C57BL/6N mice were intraperitoneally administered Auraptene(AUR),Plasma and brain samples were subsequently collected at predetermined time points.High-performance liquid chromatography(HPLC)was used to evaluate its blood-brain barrier(BBB)penetration.Mice were randomly divided into control(CON)group,model(CUMS)group,AUR(15 mg/kg)group,and fluoxetine(Flx,20 mg/kg)group,with drug intervention administered simultaneously after 4 weeks of CUMS modeling.Depressive-and anxiety-like behaviors were assessed using the sucrose preference test,open field test,three-chamber social interaction test,and tail suspension test.The expression levels of brain-derived neurotrophic factor(BDNF)in hippocampal tissues were detected by immunofluorescence and Western blot,and the contents of pro-inflammatory factors(IFN-γ,TNF-α)in hippocampal tissues were also measured.Results:Pharmacokinetic analysis showed that AUR was rapidly absorbed following intraperitoneal(i.p.)administration.The peak concentrations(Cmax)in plasma and brain tissue were observed at 30 and 45 minutes post-administration,respectively(Cmax of 1,845±127 ng/mL and 520±97.8 ng/g,respectively).Its plasma elimination half-life(t1/2)was approximately 199 min.The plasma exposure(AUC 0-240 min)over the observation period was 309,720.0 ng·min·mL-1,and the brain-to-plasma partition coefficient(Kp)was about 9.7％,indicating that AUR effectively penetrates the BBB.Behavioral assessments demonstrated that AUR intervention improved sucrose preference(P＜0.001),reduced immobility time in the tail suspension test(P＜0.001),and alleviated anxiety-like behaviors and social dysfunction(P＜0.001).Molecular and biochemical analyses revealed that AUR not only attenuated the CUMS-induced abnormal increase in hippocampal pro-inflammatory factors(e.g.,IFN-γ)(P＜0.01),but also effectively reversed the CUMS-mediated downregulation of BDNF protein expression,particularly in the DG region(P＜0.01).The comprehensive regulatory effect of AUR was comparable to that of the positive control drug,fluoxetine.Conclusion:Auraptene exhibits favorable blood-brain barrier permeability and can effectively ameliorate CUMS-induced depression,anxiety,and social withdrawal.The antidepressant mechanism of AUR may be closely associated with its actions in inhibiting neuroinflammatory responses,maintaining the neurotrophic system,and upregulating BDNF expression in the hippocampus.