Multi-targets antidepressant mechanism of the bis-benzylisoquinoline 7-O-ethylfangchinoline:Involvement of noradrenergic,dopaminergic and AMPAergic systems

OBJECTIVE Bisbenzylisoquinoline(BBI)alkaloids have extensive pharmacological functions.The aim of this study was to investigate the mechanisms underlying the antidepressant-like action of 7-O-ethylfangchinoline(YH-200)in mice.METHODS Male ICR mice were used in the forced swimming(FST)and tail suspension tests(TST).RESULTS YH-200(60mg·kg-1,ig)decreased the immobility time in FST and TST,and prolonged the latency to immobility in FST.YH-200 revealed more potent anti-immobility activity than its BBI derivative tetrandrine.In addition,the pretreatment of mice with prazosin(1mg·kg-1,ip,anα1-adrenoceptor antagonist),propranolol(2 mg·kg-1,ip,a nonselectiveβ-adrenoceptor antagonist),SCH23390(0.05mg·kg-1,ip,a dopamine D1/D5 receptor antagonist),haloperidol(0.2mg·kg-1,ip,a dopamine D2/D3 receptor antagonist)and NBQX(10mg·kg-1,ip,an AMPA receptor antagonist)prevented the antidepressant-like effect of YH-200(60mg·kg-1,ig)in FST.Besides that,the pretreatment of mice with yohimbine(1mg·kg-1,ip,an α2 adrenoceptor antagonist)augmented the antidepressant-like effect of YH-200(30mg·kg-1,ig)in FST.After 14 dadministration,YH-200(30 and 60mg·kg-1,ig)did not develop drug resistance,but the potency was strengthened,meanwhile,it did not influence the changes in mice body weight.CONCLUSION YH-200 may possess the therapeutic potential for the treatment of depression via the multi-targets including the noradrenergic(α1,α2 and β-adrenoceptors),dopaminergic(D1/D5 and D2/D3receptors)and AMPAergic systems.

Ganoderma Lucidum polysaccharide peptides protect kidney from renal ischemia reperfusion injury via counteracting oxidative stress

OBJECTIVE Ganoderma lucidum polysaccharide peptides(GLPP)have an anti-oxidant activity.The oxidative stress implicates in the pathogenesis of renal ischemia-reperfusion injury(RIRI).The objective of this study was to determine whether GLPP could attenuate RIRI via counteracting the oxidative stress.METHODS Mice subjected to uninephrectomy with the right kidney ischemia for 35 min and reperfusion for 24 hwere used to explore the protective activity of GLPP against RIRI.In GLPP-treated group,100mg·kg-1·d-1 of GLPP were intraperitoneally injected for 7dbefore the procedure.In vitro,NRK-52 Ecells subjected to hypoxia-reoxygenation(H/R)and tunicamycin were used to explore the protective effect of GLPP against oxidative stress.The mechanisms in which GLPP protected kidney from RIRI were studied using a series of physiological and molecular biological methods.RESULTS Kidneys undergone ischemia-reperfusion showed renal dysfunction and characteristic morphological changes including cellular necrosis,brush border loss,cast formation,vacuolization and tubular dilatation while these damages were significantly attenuated by GLPP treatment.The abnormal levels of MPO,MDA and SOD caused by renal ischemia-reperfusion were significantly reversed by GLPP treatment.More apoptotic cells were found in the renal ischemia-reperfusion group than the sham group whereas GLPP reduced apoptotic cells in the ischemia-reperfusion mice by21.75%(P<0.01).The GLPPs(25-1μg·mL)alleviated H/R induced cell viability loss by 20.12%(P<0.01)andΔφm dissipation by 27.3%(P<0.01)in vitro as well and its pretreatment dramatically reduced H/R and tunicamycin induced cell injury.CONCLUSION Our study found that GLPP had a protective effect on RIRI via its anti-oxidative capacity,which suggests that GLPP may be developed as a candidate drug for preventing acute kidney injury.