Comparative Study Of Rapid Antidepressant Effects Of Angiotensin Converting Enzyme Inhibitors

Objective: Angiotensin converting enzyme inhibitors(ACEI)is a commonly used first-line antihypertensive drug,via inhibiting angiotensin converting enzyme(ACE)in the renin-angiotensin system(RAS).In our previous study,we found that captopril had a significant rapid antidepressant effect in chronic unpredictable mild stress(CUMS)animal models of depression,but the duration was relatively short.We speculated that the pharmacokinetic characteristics of captopril may limit its effect.This study further investigated the effect of captopril in a chronic social defeat stress(CSDS)model,and the effect of lisinopril,a long-lasting ACEI that can pass through the BBB,on depression-like behavior in mice.Methods: Depression-like behaviors were induced in mice by constructing CSDS and CUMS animal models.Drug concentritions in plasma,cerebrospinal fluid and tissues were detected by LC-MS/MS.We assessed the depressive-like behaviors,anxiety behavior and locomotor activity through a series of behavioral tests,including sucrose preference test(SPT),tail suspension test(TST),forced swim test(FST),elevated plus maze test(EPM)and open field test(OFT).Results:(1)Intraperitoneal injection of captopril(19.5 mg/kg)and the rapid antidepressant ketamine(20 mg/kg)were used to detect the behavior of FST at 30 min,1 h,24 h,7 days and14 days after administration.Captopril did not affect the behavior of mice after 30 min and 1 h,while ketamine showed a rapid antidepressant effect after 30 min of administration,which significantly reduced the immobility time in FST(30 min,CON: 155 ± 9.124 s;Captopril: 153± 9.791 s;Ketamine: 78.5 ± 12.29 s;1 h,CON: 169.4 ± 3.779 s;Captopril: 158.4 ± 5.834 s;Ketamine: 120.1 ± 3.334 s;n = 7 – 8,p < 0.01).Captopril reduced the immobility time in FST after 24 h of administration(CON: 143.9 ± 9.503 s;Captopril: 111.8 ± 9.415 s;Ketamine:98.25 ± 10.17 s,n = 8,p < 0.05)).After 7 days of administration,captopril significantly reduced the immobility time of mice and exerted antidepressant effects(CON: 161.5 ± 4.322 s;Captopril: 108 ± 15 s;Ketamine: 99.25 ± 15.82 s,n = 8,p < 0.01)).After 14 days of administration,ketamine,but not captopril,significantly reduced the immobility time in FST(CON: 148.4 ± 5.168 s;Captopril: 139.8 ± 14.08 s;Ketamine: 89.38 ± 11.42 s,n = 8,p < 0.01).(2)Captopril improved CSDS-induced depression-like behavior.Behavioral results of social interaction at 24 h after intraperitoneal injection of captopril(19.5 mg/kg)showed that at the target stage,compared with the CON group,the time in the CSDS group in the interaction zone was significantly reduced(CON: 81.04 ± 6.179 s;CSDS: 40.20 ± 7.190 s;n = 10-13,p <0.01).Compared with the CSDS group,the time in the interaction zone of the CSDS +Captopril group was significantly increased(CSDS: 40.20 ± 7.190 s;CSDS + Captopril: 66.28± 10.284 s;n = 12-13,p < 0.05).The social interaction ratio of CSDS group was significantly lower than that in CON group(CON: 1.36 ± 0.086;CSDS: 0.60 ± 0.096;n = 10-13,p < 0.01).The social interaction ratio of the CSDS + Captopril group was higher than that in vehicle group(CSDS: 0.60 ± 0.096;CSDS + Captopril: 1.32 ± 0.144;n = 12-13,p < 0.01).(3)The levels of captopril in the m PFC were measured using liquid chromatography-tandem mass spectrometry following the peripheral administration of captopril(19.5 mg/kg).The plasma concentrations of captopril reached peak levels(184.06 ± 20.25 ng/m L,n = 11)at 0.5 h after administration.In this experimental condition,the detection limit of captopril concentration was 23.01 n M.(4)Linopril exerted a rapid antidepressant effect in normal mice and significantly reduced the immobility time in FST(CON: 160.75 ± 14.599 s;Captopril(19.5mg/kg): 116.5 ± 6.299 s;Lisinopril(39.6 mg/kg): 114.88 ± 6.553 s;Lisinopril(79.2 mg/kg):102.5 ± 8.633 s;n = 8,p < 0.01).We found that in addition to the rapid antidepressant effect of lisinopril,the duration of its antidepressant effect lasted for about a week,and lisinopril at the low dosage(39.6 mg/kg)reduced the immobility time in TST in normal mice(2 h: CON: 131.1± 10.14 s;Lisinopril: 83.95 ± 11.2 s;12 h: CON: 151.7 ± 9.455 s;Lisinopril: 86.95 ± 14.75 s;7d: CON: 186.4 ± 10.56 s;Lisinopril: 123.9 ± 10.78 s;14 d: CON: 185.3 ± 11.17 s;Lisinopril:184.8 ± 12.6 s;n = 10-12,p < 0.01).Lisinopril(39.6 mg/kg,at the same molar equivalent dose of 19.5 mg/kg captopril)exerted similar rapid antidepressant activities of captopril in the FST at different time points after administration.Lisinopril’s rapid antidepressant effect was more obvious,and the duration of antidepressant effect was longer(30 min: CON: 133.75 ±13.28 s;Captopril: 120 ± 6.51 s;Lisinopril: 110 ± 6.86 s;2 h: CON: 148.6 ± 7.04 s;Captopril:124.5 ± 9.30 s;Lisinopril: 118.4 ± 5.00 s;7 d: CON: 150.8 ± 6.50 s;Captopril: 107.5 ± 10.67 s;Lisinopril: 89.25 ± 9.71 s;14 d: CON: 149 ± 8.50 s;Captopril: 131.9 ± 6.32 s;Lisinopril:105.5 ± 11.26 s;n = 8,p < 0.01).(5)The mice exposed to CUMS were injected intraperitoneally with captopril(19.5 mg/kg)or lisinopril(39.6 mg/kg),and the sucrose preference test was performed at 2 h,12 h and 7 d after administration.Lisinopril reversed the sucrose preference of CUMS mice after 2 h of administration(CON: 87.62 ± 2.807%;CUMS:44.14 ± 11.269%;CUMS + Captopril: 40.69 ± 8.664 %;CUMS + Lisinopril: 78.33 ± 7.979%;n = 7-8,p < 0.01).Captopril significantly improved the sucrose preference caused by CUMS after 24 h of administration(CON: 86.47 ± 1.898%;CUMS: 47.71 ± 4.017%;CUMS +Captopril: 79.45 ± 2.416%;CUMS + Lisinopril: 82.27 ± 2.199%;n = 8-16,p < 0.01).Both captopril and lisinopril significantly increased the sucrose preference of CUMS mice after 7 d of administration(CON: 85.24 ± 2.588%;CUMS: 58.05 ± 3.669%;CUMS + Captopril: 78.33± 5.243%;CUMS + Lisinopril: 83.89 ± 5.986%;n = 7-14,p < 0.01).(6)Linopril did not affect the anxiety-like behavior and spontaneous activity of mice in elevated plus maze and open field experiments.Conclusion: Lisinopril exerts a rapid antidepressant effect in mice.The effect of lisinopril is faster and the duration is more durable than captopril in the CUMS-treated mice,suggesting that long-lasting ACEIs may be used as new rapid-onset antidepressants.