摘要
Aim To investigate the effects of YL- IPA08 on the endogenous metabolites of PTSD model rats by metabolomics methods, and to explore the metabolic pathways and possible mechanisms of YL-IPA08 against PTSD. Methods The rats were randomly divided into control group, PTSD model group, and administration group of PTSD rats induced by forced swimming test, and the treatment group was given YL- IPA08 (2 mg • kg"1) by intragastric gavage for 15 consecutive days. High-performance liquid chromatog- raphy-mass spectrometry (HPLC-MS/MS) technology was used to detect the endogenous differential metabolites and the associated metabolic pathways in rat plasma samples. Targeted quantitative technology was simultaneously applied to detect the concentrations of 18 bile acids in rat plasma. Results Compared with control group, 40 kinds of endogenous metabolites including glutamic acid, proline, valine, arginine, leucine , cholic acid, and creatine showed significant difference, and the concentrations of 11 bile acids significantly increased in plasma of model group as well. Compared with model group, after YL-IPA08 intervention , the above-mentioned potential metabolites ap-peared to return to normal levels. Conclusions Metabolomics analysis reveals that YL-IPA08 has intervention effect on PTSD model rats. The mechanism may be related to the regulation of amino acid metabolism and bile acid metabolism.
摘要
OBJECTIVE: To study the effect of Mr1.8×104 translocator protein (TSPO) selective ligand compound YL-IPA08 on postpartum anxiety-depressive behavior. METHODS: The model of postpartum depression in rats was established by classical hormone simulating postpregnancy (HSP) hormone withdrawal induced, and the effect of YL-IPA08 on spontaneous activity in rats was evaluated by the open field test(OFT), and the effect of YL-IPA08 on anxiety and depressive-like behavior in rats was evaluated by the elevated plus maze test (EPM) and forced swimming test (FST). The changes of TSPO expression in hippocampuls and prefrontal cortex of rats were detected by RT-PCR and Western blot. RESULTS: Compared with control group, the hormones of pregnancy hormones withdraw stimulating and drug treatment do not affect the spontaneous activity of rats (P>0.05), but the model group rats showed significant anxiety and depressive symptoms, which is characterized by elevated plus maze test (P<0.05, P<0.01),and forced swimming test (P<0.05).After the establishment of the model, three weeks of intragastric administration were started, YL-IPA08 (0.1 and 0.3 mg•kg-1, po) or positive control drug sertraline (10 mg•kg-1, po) can significantly reverse the above series of changes of postpartum anxiety and depressive behavior (P<0.05 or 0.01), and significantly increase the TSPO level in the hippocampus and prefrontal cortex of the model rats. CONCLUSION: YL-IPA08 shows anti-postpartum anxiety-depressive behavior in a series of rat behavior models, and the mechanism may be closely related to its enhancing central TSPO expression and promoting biosynthesis of following neurosteroids.
摘要
Objective To explore the anti-post-traumatic-stress-disorder(anti-PTSD)effects of YL-IPA08,a selective 18kDa translocator protein(TSPO)ligand.Methods The time-dependent stress sensitization(TDS)method was used to establish a rat mod?el of PTSD.The open field test(OFT)was used to evaluate the locomotor activity in rats.The contextual freezing(CF)measurement, elevated plus maze(EPM)test and novel objective recognition(NOR)test were used to evaluate the PTSD-like behaviors in rats.The concentration of allopregnanolone in rat hippocampus was detected by ELISA. Results Compared with the control group,neither TDS nor drug treatment affected the locomotor activity in rats(P>0.05).However,PTSD rats showed significant PTSD-like behaviors with enhanced CF time in CF mearsurement,decreased open arm time and open arm entries in EPM test,and dropped object recogni?tion index in NOR test(P<0.05 or 0.01).Moreover,the concentration of hippocampus allopregnanolone was decreased in PTSD rats (P<0.05).YL-IPA08(0.05-0.1mg/kg)or positive drug sertraline(15 mg/kg),administered intragastrically after establishment of PTSD model,significantly reversed the above PTSD-like behavioral changes(P<0.05 or 0.01)and increased the concentration of hip?pocampus allopregnanolone in PTSD rats.Conclusion YL-IPA08 could improve the PTSD-like behavior in rats,and the mechanism may be related to the increased allopregnanolone level in hippocampus.
摘要
Objective To explore the role of 18 ku translocator protein (TSPO) in the anti-post-traumatic-stress-disorder(PTSD) effects of YL-IPA08 and the value of TSPO as a potential pharmacological target using gene knock out mice.Methods The PCR method was used to genotype TSPO wild type (WT) mice and knock out (KO) mice.Foot shock was used to establish a well-accepted mouse model of PTSD,the open field test (OFT) was used to evaluate the locomotor activity in mice,and freezing measurement was used to evaluate the PTSD-like fear behavior in mice.Results Compared with TSPO WT mice,KO mice had no expressible TSPO gene,but showed similar locomotor activity to WT mice after PTSD modeling.On day 1,day 5 and day 16 after PTSD modeling (day-1-day 0),both WT and KO mice showed significant PTSD-like behavior with enhanced freezing time.However,8 d treatment (day 0-day 7) of YL-IPA08 (0.3 mg/kg,once daily) or positive drug sertraline (15 mg/kg,once daily) after PTSD modeling significantly reduced freezing time selectively in WT mice,but not in KO mice.Conclusion It has been found for the first time that TSPO WT and KO mice can show the same sensitivity to PTSD modeling (namely the same PTSD-like behavior performance).Interestingly,TSPO can mediate the anti-PTSD effects of YL-IPA08.Therefore,the present study provides direct evidence for the value of TSPO as an potential pharmacological target for PTSD.
摘要
OBJECTIVE To investigate the protective effect of selective 18 ku translocator protein (TSPO) ligand YL-IPA08 on corticosterone(CORT)-induced apoptosis of BV-2 cells and its potential mecha?nisms. METHODS BV-2 Cells were pretreated with selective TSPO ligand YL-IPA08 1-100 nmol · L-1 and(or) TSPO antagonist PK11195 100 nmol · L-1 for 2 h,and then co-incubated with CORT for another 24 h. The apoptosis rate was measured by flow cytometry. CCK-8 kit was used to test BV-2 cell viability. The protein expression of TSPO was determined by Western blotting. The level of allopreg?nanolone was detected by ELISA kit. RESULTS In line with positive drug-AC-5216, the cell apoptosis rate decreased in YL-IPA08 1-100 nmol · L-1 and CORT co-treatment groups(P<0.01), which was antago?nized by PK11195 100 nmol · L-1 treatment(P<0.05). Cell viability increased in YL-IPA08 100 nmol · L-1and CORT co-treatment groups (P<0.01), which was blocked by PK11195 100 nmol·L-1 treatment(P<0.01). The expression of TSPO and the level of allopregnanolone(P<0.01) were enhanced by YL-IPA08 100 nmol · L-1 pretreatment followed by CORT treatment. The enhancement of allopregnanolone level was blocked by PK11195 100 nmol·L-1 treatment(P<0.05). CONCLUSION YL-IPA08 can protect BV-2 cells from CORT induced apoptosis. The protective effect of YL-IPA08 may be conferred by the increasing level of TSPO expression and allopregnanolone.