| PartⅠ Effects of different charges of electroconvulsive shock under low-dose ketamine combined with propofol anaesthesia on depressive-like behavior and function function in depressive ratsObject To investigate the effects of different charges of electroconvulsive shock under low-dose ketamine combined with propofol anaesthesia(hereinafter referred to as compound anesthetics) on depressive-like behavior and function function in depressive rats, so as to help optimize treatment regimens.Methods Fifty-six healthy adult male Sprague-Dawley rats(200-250 g; 2-3 months old) were included and chronic unpredictable mild stress(CUMS) procedure to establish a model of depression. After the CUMS procedure to be completed, one group of depressive rats was used for the measurement of seizure threshold in ECS with the compound anesthetics(Group ST, n=8). The other depressive rats were allocated to six groups(n=24):(1) The rats in Group D only received normal saline solution(8 m L/kg, i.p.) once a day;(2) After treatment with the same anesthetic protocol[ketamine(10 mg/kg) and propofol(80 mg/kg), i.p.], five groups(group M0, M60, M120, M180 and M240, respectively) of the depressive rats received ECS treatment with different stimulus intensities(i.e. charges, 0, 60, 120, 180 or 240 m C). The aforementioned treatments were given once a day for 7 days. Sucrose preference test, open-field test and Morris water maze were used to assess behavioral changes.Results(1)The seizure threshold of the depressive rats that received compound anesthesia was 41.25± 5.50 m C.(2)The sucrose preference percentage(SPP), the number of crossing and the number of rearing in each group exhibited a significantly decrease after the CUMS procedure(P<0.05), but had no significant differences between these groups(P>0.05). After rats received ECS treatment at different charges, SPP, the number of crossing and the number of rearing in groups M60, M120, M180 and M240 were significantly increased in comparison with those before MECS treatments(P<0.05). However, these values among groups M120, M180 and M240 had no significant differences(P>0.05). Compared with group M60, these values in group M120 was in increased(P<0.05). Meanwhile, there were no significant differences in SPP, the number of crossing and the number of rearing between groups D and M0(P>0.05).(3)During the MWM test, the swimming speed of depressive rats had no significant differences among these groups(P>0.05). After the MECS treatments, the time to find the platform in group M120 was shorter than other group(P<0.05). Meanwhile, group M0 had no significant decrease of escape latency(EL) as compared with group D(P>0.05). When the platform was removed for spatial memory testing, group M120 also had significantly longer dwelling times in the former platform quadrant(P<0.05). No differences were found in comparisons between group D and group M0(P>0.05).Conclusions 120 m C ECS with the compound anesthetics is the optimal option for the depressive rats. Part Ⅱ Propofol ameliorates electroconvulsive seizure induced memory dysfunction in depressive ratsObject To investigate the effects of propofol and electroconvulsive on depressive-like behavior and cognitive function as well as tissue plasminogen activator(t PA),plasminogen activator inhibitor-1(PAI-1),the precursor of brain-derived neurotrophic factor(pro BDNF) and mature BDNF(m BDNF) in depressive rats.Methods Sixty healthy adult male Sprague-Dawley rats(200-250 g; 2-3 months old) were randomly assigned to 5 groups(n=12 in each group): control group(group C), depression model group(group D), ECS group(group DE), propofol group(group DP) and propofol + ECS group(group DPE). Group C was the control group of healthy rats without treatment; the rats in other groups were treated with the CUMS procedure to establish a model of depression. After the CUMS procedure to be completed, rats in group D were given Normal saline(8ml/kg, i.p.) and then subjected to sham ECS treatment; rats in group DE were given Normal saline(8ml/kg, i.p.) and then subjected to ECS treatment; rats in group DPE were given propofol(80 mg/kg, i.p.) and then subjected to ECS treatment; rats in group DP were given propofol(80 mg/kg, i.p.) and then subjected to sham ECS treatment. The sham ECS was handled identically as ECS without current. The aforementioned treatments were given once a day for 7 days. Sucrose preference test, open-field test and Morris water maze were used to assess behavioral changes. The neural numbers were measured by Nissl staining. The expression levels of pro BDNF and m BDNF in CA1 hippocampus were measured by immunofluorescence, the expression levels of pro BDNF, m BDNF, t PA and PAI-1 were measured by western blot.Results(1)After the CUMS procedure, the values of SPP, the number of crossing and the number of rearing of the four CUMS-treated groups were lower than that of group C(P < 0.05), and no significant differences were found in these values among the CUMS-treated groups(P > 0.05). After administering ECS treatment to the rats, these values in groups DE and DPE were higher than in group D(P < 0.05). In addition, no significant differences were found in the values of SPP between groups DE and DPE(P > 0.05). However, the number of crossing and the number of rearing in group DPE were lower than that of group DE(P < 0.05). No significant differences were found in the values of SPP, the number of crossing and the number of rearing between groups D and DP(P > 0.05).(2)After administering the ECS and propofol treatments to the groups, no significant difference was noted in the swimming speed among these groups during the Morris water maze(MWM) test(P > 0.05). The EL was shorter in group C than in the other groups(P < 0.05). Meanwhile, the latencies of groups DE and DPE were significantly longer than that of group D(P < 0.05). However, the EL was shorter in group DPE than in group DE(P < 0. 05). No significant difference was observed in the latency between groups D and DP(P > 0.05). In the probe trial test, the rats in group C exhibited significantly longer dwelling times in the target quadrant compared with those in the other groups(P < 0.05), and the rats in group DE exhibited shortened space exploration time(SET) compared with those in group DPE(P < 0.05). Nevertheless, no significant difference was observed in SET between groups D and DP(P > 0.05).(3) Quantitative data found that the numbers of CA3 cells of four CUMS-treated groups were less than that of group C(P < 0.05), and no significant differences in the numbers of CA3 cells were found among the CUMS-treated groups(P > 0.05).(4) The expression of pro BDNF and m BDNF in the CA1 region was examined by fluorescence microscopy. The depressive rats(group D) had more pro BDNF and less m BDNF expression compared with the group C rats in this region(P < 0.05). The immunoreactive spots of pro BDNF and m BDNF increased after the ECS treatment(group DE)(P < 0.05). Propofol increased the number of m BDNF–immunoreactive spots in the rats receiving ECS treatment(group DPE)(P < 0.05).(5) After administering ECS treatment to the rats, the hippocampal m BDNF and t PA levels significantly decreased in group D compared with group C(P < 0.05). In contrast, the expression of pro BDNF and PAI-1 increased in group D compared with those in group C(P < 0.05). Meanwhile, the expression of m BDNF、pro BDNF and t PA in group DE markedly increased compared with those in group D(P<0.05). Additionally, group DPE exhibited a higher level of m BDNF, a lower expression of pro BDNF in the hippocampus compared with group DE(P < 0.05).Conclusions The results of this study suggest that ECS has a good antidepressant effect, but can result in learning and memory impairment. Propofol ameliorates cognitive decline induced by ECT, but it moderately weakened the antidepressant effect of ECS. The protective effect producted by propofol might be involved in modulating the expression of t PA, resulting in a decreased pro BDNF/m BDNF ratio in hippocampus. Part Ⅲ Low-dose ketamine combined with propofol ameliorates electroconvulsive seizure-induced memory impairment by modulating t PA-BDNF pathway in depressive ratsObject To investigate the effects of low-dose ketamine combined with propofol on depressive-like behavior and cognitive function, as well as t PA, PAI-1,pro BDNF and m BDNF, in depressive rats undergoing electroconvulsive shock. So as to elucidate the underlying molecular mechanisms of low-dose ketamine combined with propofol alleviate ECS-induced cognitive function.Methods Forth-eight healthy adult male Sprague-Dawley rats(200-250 g; 2-3 months old) were included and chronic unpredictable mild stress(CUMS) procedure to establish a model of depression. After the CUMS procedure to be completed, rats were randomly assigned to 4 groups(n=12 in each group): propofol + ECS group(group DPE), propofol + ketamine + ECS group(group DPKE), PAI-1+ propofol + ketamine + ECS group(group DPKEI) and normal saline+ propofol + ketamine + ECS group(group DPKEV). Rats in group DPE were given propofol(80 mg/kg, i.p.) and then subjected to ECS treatment; rats in group DPKE were given propofol(80 mg/kg, i.p.) plus ketamine(10 mg/kg, i.p.), and then subjected to ECS treatment; before the intraperitoneally injected with ketamine and propofol, rats in group DPKEI and group DPKEI were pretreated with PAI-1 and normal saline intrahippocampal injection, respectively. The aforementioned treatments were given once a day for 7 days. Sucrose preference test, open-field test and Morris water maze were used to assess behavioral changes.Results(1)The SPP, the number of crossing and the number of rearing in each group exhibited a significantly decrease after the CUMS procedure(P<0.05), but had no significant differences between these groups(P>0.05). After administering ECS treatment to the rats, these values in groups DPKE and DPKEV were higher than in group DPE(P < 0.05). In addition, no significant differences were found in the values of SPP between groups DPKE and DPKEV(P > 0.05). However, these values in groups DPKEI were higher than in group DPE(P < 0.05).(2)After administering the ECS treatments to the groups, no significant difference was noted in the swimming speed among these groups during the Morris water maze(MWM) test(P > 0.05). The latencies of groups DPKE and DPKEV were significantly shorter than that of group DPE(P < 0.05). However, the EL was shorter in group DPE than in group DE(P < 0. 05). No significant difference was observed in the latency between groups DPKE and DPKEV(P > 0.05). In the probe trial test, the SET of groups DPKE and DPKEV were significantly longer than that of group DPE(P < 0.05). However, the rats in group DPKEI exhibited shortened SET compared with that in group DPE(P < 0.05). Nevertheless, no significant difference was observed in SET between groups DPKE and DPKEV(P > 0.05).(3) After administering ECS treatment, the rats in DPKE and DPKEV had more m BDNF and less pro BDNF expression compared with the group DPE(P < 0.05). However, the rats in DPKEI had more pro BDNF and less m BDNF expression compared with the group DPE(P < 0.05). Compared with group DPE, the levels of t PA in other groups were much higher(P < 0.05), and no significant differences in the level of t PA were found among groups DPKE, DPKEV and DPKEI(P > 0.05). Compared with group DPKEI, the levels of PAI-1 in other groups were much lower(P < 0.05), and no significant differences in the level of PAI-1 were found among groups DPE, DPKE and DPKEV(P > 0.05).Conclusions The results of this study suggest that, compared with propofol anesthesia, low-dose ketamine combined with propofol could enhance the antidepressant efficacy and further improve the cognitive performance after ECS in depressive rats. The protective effect producted by propofol might be involved in modulating the expression of t PA, resulting in a decreased pro BDNF/m BDNF ratio in hippocampus. |
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