Neuroprotective effect of nobiletin on cognitive dysfunction rats after sevoflurane anesthesia / 中华行为医学与脑科学杂志

ABSTRACT

Objective:To study the neuroprotective effect of nobiletin on the symptoms of postoperative cognitive impairment (POCD) induced by sevoflurane inhalation.Methods:Twenty-four aged SD rats (12 female mice and 12 male mice) were divided into three groups randomly control group ( n=8), surgery group ( n=8) and surgery + nobiletin group ( n=8), with 4 females and 4 males in each group.The rats in surgery group and surgery+ nobiletin group were given normal saline(0.1 ml/10 g, once a day) and nobiletin(100 mg/kg, once a day) intragastrically for 6 weeks.Then the rats were anesthetized by sevoflurane and treated by abdominal exploration surgery, and then continued gavage for 1 week.The rats in control group were given normal saline(0.1 ml/10 g, once a day) intragastrically for 7 weeks without anesthesia or surgery.Sevoflurane inhalation anesthesia and abbreviated laparotomy were not done for control group.Morris water maze and open field experiment were used to measure the memory and cognitive ability and the independent exploration ability respectively.The changes of α-band electroencephalogram (EEG) were recorded by multi-channel physiological signal acquisition and processing system.The concentration of S100β, a marker of neurological impairment was detected by ELISA.Western blot was used to detect the expression level of IBA-1 in microglia.SPSS 20.0 software was used to analyze the data. Results:There were no significant differences in Morris water maze, positioning cruise test and open field test among the groups before operation (all P>0.05). The differences were statistically significant among the groups 7 days after operation (all P<0.05). Compared with the control group (the escape latency, path length and cross platform times were ((20.37±1.11)s, (552.37±14.19)cm, (6.75±0.43)times respectively), the escape latency ((40.87±2.03)s) and path length ((1 258.62±19.53)cm) of rats in surgery group were significantly longer (both P<0.01), and the cross platform times ((2.12±0.33)times) significantly reduced ( P<0.01). The differences between surgery + nobiletin group ((22.37±1.11)s, (584.50±10.90)cm, (6.62±0.48)times) and control group were not significant (all P>0.05). The open field experiment showed that the movement distance, the crossed square number, and activity times in surgery group ((1.78±0.55) m, (4.75±0.50), (14.87±0.33) times) decreased significantly compared with those in control group ((3.73±0.07) m, (11.10±0.78), (51.12±0.78) times, all P<0.01). No significant difference was found between surgery + nobiletin group ((3.76±0.07)m, (10.75±0.66), (50.75±0.43)times) and control group(all P>0.05). Before anesthesia, there was no significant difference in the power ratio of α-band among the three groups ( P>0.05), but the differences during anesthesia and operation were significant ( F=72.58, 101.50, P<0.01). During anesthesia and operation, the power ratio of α-band in anesthesia and in surgery group (2.51±0.04, 2.14±0.03) were significantly lower (both P<0.01) than those in control group (3.49±0.03, 3.49±0.03), while there was no obvious changes (both P>0.05) in the surgery + nobiletin group (3.50±0.04, 3.51±0.04). There were significant differences in Bcl-2 protein expression and caspase 3/7 protein activity among the three groups ( F=5.21, 7.84, P<0.01). Compared with control group (1.00±0.02, 1 557.46±3.63), Bcl-2 of rats in the surgery group(0.40±0.05) were significantly lower and Caspase3/7 expression of surgery group (3 689.58±10.46) was significantly higher (both P<0.01), while the rats in the surgery + nobiletin group had no significant difference in both Bcl-2 level (1.03±0.06) and caspase 3/7 activities (1 805.28±6.17, both P>0.05). The difference of S100 β protein expression was significant among the three groups ( F=490.80, P<0.01). Compared with the control group ((0.18±0.01)μg/L), the concentration of S100β protein in the surgery group ((2.13±0.02)μg/L) decreased ( P<0.01), while there was no significant difference in the surgery + nobiletin group ((0.16±0.01) μg/L, P>0.05). The expression levels of IBA-1 protein ( F=10.83) and TNF-α, IL-1, IL-1β and IL-6 ( F=996.20, 221.40, 73.02, 174.13) were significantly different among the three groups (all P<0.01). The expression level of the neuroglial marker IBA-1 in the surgery group(1.36±0.02) was significantly higher than that in the control group (1.00±0.01, P<0.01), while the surgery + nobiletin group (1.03±0.01) had no significant different compared with control group ( P>0.05). The levels of inflammatory factors, including TNF-α, IL-1, IL-1β and IL-6, in the brain of rats treated with nobiletin ((49.06±3.63)pg/mg, (2.09±0.43)pg/mg, (16.27±0.80)pg/mg, (2.11±0.19)pg/mg) were significantly lower than those in the surgery group((145.10±6.46)pg/mg, (5.67±0.43)pg/mg, (27.88±3.43)pg/mg, (4.74±0.32)pg/mg, all P<0.01). Conclusion:Nobiletin can obviously alleviate POCD symptoms caused by sevoflurane inhalation anesthesia.