丙泊酚对氯胺酮诱导大鼠抗抑郁样作用的影响
摘要
目的:氯胺酮是一种临床上广泛用于镇痛的静脉麻醉药,是非竞争性N-甲基-D-天(门)冬氨酸(NMDA)受体拮抗剂。近年来,临床及动物试验均发现氯胺酮可以产生强大,快速且相对持久的抗抑郁样作用,其抗抑郁样作用与拮抗中枢兴奋性氨基酸NMDA受体和增强海马脑源性神经营养因子(BDNF)表达相关。但氯胺酮可诱发拟精神症状和认知损害,部分与其诱发超氧化物持续表达有关,因此抗超氧化物可能是治疗氯胺酮副作用的靶点之一。全麻药物丙泊酚具有抗超氧化物作用和剂量依赖式抑制NMDA受体NR1亚基磷酸化作用,该受体磷酸化在NMDA受体功能的激活中发挥重要作用。故推测丙泊酚与氯胺酮配合使用,是否有可能在减少氯胺酮副作用的同时增强氯胺酮诱导的抗抑郁样作用。为证实此推测,本实验通过观察预先注射丙泊酚后氯胺酮对大鼠行为学习性及强迫游泳大鼠海马BDNF表达水平影响的变化,为临床丙泊酚配合氯胺酮治疗抑郁症以及缓解抑郁症患者术后抑郁提供理论依据。方法:将100只大鼠按照完全随机设计分为I,II两组,每组50只。I组行旷场试验, II组行强迫游泳试验,剔除预试验中不合格者,每组选取42只随机分为7个小组,每小组6只大鼠:生理盐水(A)组;氯胺酮20mg/kg(B)组;丙咪嗪30mg/kg(C)组;丙泊酚10 mg/kg(D)组;丙泊酚20 mg/kg(E)组;丙泊酚10 mg/kg+氯胺酮20mg/kg(F)组;丙泊酚20 mg/kg+氯胺酮20mg/kg(G)组。以上药物均在进行旷场试验或强迫游泳试验前1小时经腹腔注射给予,所有药物稀释成3ml,F组和G组丙泊酚与氯胺酮注射间隔时间为15min。旷场试验箱为一个66cm×50cm×40cm的箱体,箱底画有25个相等方格(13×10cm)。每组大鼠经腹腔注射给予相应药物1h后,将大鼠置于试验箱中央格内,观察并记录5min内大鼠的累计穿格数和直立次数。强迫游泳试验是将大鼠单个放入水深为20cm的玻璃圆筒(高50 cm,直径20 cm)中,水温23-25℃,水深可稍作调整,以大鼠后足刚可触及筒底又不足以支撑身体为宜。每换一只大鼠更换一次水。强迫游泳试验进行两次,第一次为预游泳,各组均不给药,将大鼠逐一放入玻璃圆筒中游泳15min。预游泳24h后,每组大鼠经腹腔注射给予相应药物。1h后,在与预游泳条件完全相同的情况下,将大鼠放入圆筒中,记录5min内大鼠强迫游泳的累计不动时间,以秒为单位。在第二次强迫游泳试验结束后,立即处死大鼠分离出海马组织,匀浆取上清液,在-20℃下冻存备测。利用双抗体夹心酶联免疫吸附(ELISA)实验检测强迫游泳大鼠海马BDNF水平。结果:①旷场试验:B、C、D、E、F、G组大鼠的累计穿格数和直立次数与A组相比差异无统计学意义( n=6, P>0.05)。②强迫游泳试验:A组的不动时间为(132.67±5.13)s, B组的不动时间为(68.17±6.05)s, C组的不动时间为(97.33±10.88)s, D组的不动时间为(126.50±4.09)s, E组的不动时间为(124.83±7.65)s, F组的不动时间为(54.67±8.29)s, G组的不动时间为(55.83±6.11)s。与A组相比,B、C、F和G组可以缩短大鼠不动时间,具有统计学差异( n=6, P<0.01);其中B、F、G组与C组相比,不动时间缩短,具有统计学差异( n=6, P<0.01);F、G组与B组相比,不动时间缩短,差异具有统计学意义( n=6, P<0.01);而D组、E组,与A组相比,差异则无统计学意义( n=6,P>0.05)。③大鼠海马BDNF水平:A组的BDNF水平为(84.50±4.85)pg/ml, B组的BDNF水平为(118.33±4.68)pg/ml, C组的BDNF水平为(89.67±4.68)pg/ml, D组的BDNF水平为( 80.17±4.49 ) pg/ml, E组的BDNF水平为(79.17±4.36)pg/ml, F组的BDNF水平为(115.00±6.20)pg/ml,G组的BDNF水平为(113.67±5.89)pg/ml,其中B、F、G组与A组比较,差异有统计学意义(n=6, P<0.05);C、D、E组与A组相比差异无统计学意义(n=6, P>0.05);F、G组与B组比较差异无统计学意义( n=6,P>0.05)。结论:丙泊酚可增强大鼠强迫游泳试验中急性注射氯胺酮诱导的抗抑郁样作用,但可能并非通过海马BDNF起作用。
Objective: Ketamine is a non-competitive antagonist to the phencyclidine site of N-methyl-D-aspartate (NMDA) receptor. Clinical findings and animal experiments point to a rapid onset of action for ketamine on the treatment of major depression and suggest that the NMDA receptor and acute increase of brain-derived-neurotrophic factor (BDNF) protein levels in hippocampus might be critical to the antidepressant-like effects induced by ketamine. Ketamine has been demonstrated to induce schizophrenia-like symptoms and cognitive impairment in humans, partly resulting from persistent increase in brain superoxide caused by ketamine. Anti-superoxide may represent a novel target for the treatment of ketamine-induced psychosis. Propofol ( 2,6-diisopropylphenol ) is a general anesthetic possessing actions inhibiting phosphorylation of NMDA Receptor NR1 Subunits and against oxidative stress in neurons, so the agent is presumed to interact with ketamine and hence to enhance the antidepressant-like effects involved in ketamine. Therefore, to test the possibility, this experiment has examined the behavioral effects and the BDNF protein levels in hippocampus of acute administration of ketamine and acute administration of ketamine after propofol pretreatment in rats. Methods: Rats were randomly divided into group I and group II (n=50/each), Rats in group I or II were again randomly divided into group A (sodiumChloride), group B (ketamine 20mg/kg), group C (imipramine 30mg/kg), group D (propofol 10mg/kg), group E (propofol 20mg/kg), group F (propofol 10mg/kg+ketamine 20mg/kg) and group G (propofol 20mg/kg+ketamine 20mg/kg ) (n=6/each). Rats in different groups were administered intraperitoneally (i.p.) with the corresponding drugs 60 minutes before the test sessions, i.e. open-field or forced swimming tests. All treatments were administered in 3ml volume. In group F and G, the interval time between propofol and ketamine administration was 15 min. In the open-field test, rats were treated with the corresponding drugs 60 min before the exposure to the open-field apparatus, in order to assess possible effects of drug treatment on spontaneous locomotor activity. Analysis of rat spontaneous activity was carried out in an open cardboard box, which is an arena 66×50 cm surrounded by 40 cm high walls. The floor of the open field was divided into 25 rectangles (13×10cm each) by black lines. Animals were gently placed on the center of floor, and left to explore the arena for 5 min. The number of horizontal (crossings) and vertical (rearings) activity performed by each rat during the 5 min observation period was counted. The forced swimming test involves two individual exposures to a cylindrical tank with water in which rats cannot touch the bottom of the tank or escape. The tank is made of transparent Plexiglas, 50 cm tall, 20 cm in diameter, and filled with water ( 23-25°C ) to a depth of 20 cm. Water in the tank was changed after each rat. For the first exposure, rats without drug treatment were placed in the water for 15 min ( pre-test session ). Twenty-four hours later, rats were placed in the water again for a 5 min session ( test session ), and the immobility time of rats were recorded in seconds. Rats were treated with ketamine, propofol + ketamine, imipramine or saline only 60 min before the second exposure to the cylindrical tank of water ( test session ). Immediately after the forced swimming test, acutely saline, ketamine, propofol + ketamine, imipramine -treated rats were sacrificed and the skulls were removed and hippocampus was dissected and stored at -20℃for biochemical analyses. The BDNF protein levels in hippocampus were measured by anti-BDNF sandwich-ELISA . Results:①Open-field test: In this test, the treatment with ketamine,propofol+ketamine and imiprimine did not modify the number of crossings and rearings compared with saline treated-rats ( n=6, P>0.05);②Forced swimming test:The immobility time in group A, B, C, D, E, F, G was (132.67±5.13), (68.17±6.05),(97.33±10.88),(126.50±4.09), (124.83±7.65), (54.67±8.29) and (55.83±6.11) s, respectively. The immobility time in group B, C, F, G was lower than that in group A ( n=6, P<0.01); Compared with group C,the immobility time in group B, F, G was decreased ( n=6, P<0.01); The immobility time in group F, G was also lower than that in group B ( n=6, P<0.01).③The BDNF protein levels in hippocampus measured by anti-BDNF sandwich-ELISA: the BDNF levels in hippocampus in group A, B, C, D, E, F, G was (84.50±4.85), (118.33±4.68), (89.67±4.68), (80.17±4.49), (79.17±4.36), (115.00±6.20) and (113.67±5.89) pg/ml, respectively. the BDNF levels in hippocampus in group B, F, G was higher than that in group A (n=6, P<0.05), but had no differences among group B, F, G (n=6, P>0.05). Conclusions: Propofol could increase the antidepressant-like effects induced by acute administration of ketamine in rats, but the mechanism might not be not related to the BDNF levels in hippocampus.
Objective: Ketamine is a non-competitive antagonist to the phencyclidine site of N-methyl-D-aspartate (NMDA) receptor. Clinical findings and animal experiments point to a rapid onset of action for ketamine on the treatment of major depression and suggest that the NMDA receptor and acute increase of brain-derived-neurotrophic factor (BDNF) protein levels in hippocampus might be critical to the antidepressant-like effects induced by ketamine. Ketamine has been demonstrated to induce schizophrenia-like symptoms and cognitive impairment in humans, partly resulting from persistent increase in brain superoxide caused by ketamine. Anti-superoxide may represent a novel target for the treatment of ketamine-induced psychosis. Propofol ( 2,6-diisopropylphenol ) is a general anesthetic possessing actions inhibiting phosphorylation of NMDA Receptor NR1 Subunits and against oxidative stress in neurons, so the agent is presumed to interact with ketamine and hence to enhance the antidepressant-like effects involved in ketamine. Therefore, to test the possibility, this experiment has examined the behavioral effects and the BDNF protein levels in hippocampus of acute administration of ketamine and acute administration of ketamine after propofol pretreatment in rats. Methods: Rats were randomly divided into group I and group II (n=50/each), Rats in group I or II were again randomly divided into group A (sodiumChloride), group B (ketamine 20mg/kg), group C (imipramine 30mg/kg), group D (propofol 10mg/kg), group E (propofol 20mg/kg), group F (propofol 10mg/kg+ketamine 20mg/kg) and group G (propofol 20mg/kg+ketamine 20mg/kg ) (n=6/each). Rats in different groups were administered intraperitoneally (i.p.) with the corresponding drugs 60 minutes before the test sessions, i.e. open-field or forced swimming tests. All treatments were administered in 3ml volume. In group F and G, the interval time between propofol and ketamine administration was 15 min. In the open-field test, rats were treated with the corresponding drugs 60 min before the exposure to the open-field apparatus, in order to assess possible effects of drug treatment on spontaneous locomotor activity. Analysis of rat spontaneous activity was carried out in an open cardboard box, which is an arena 66×50 cm surrounded by 40 cm high walls. The floor of the open field was divided into 25 rectangles (13×10cm each) by black lines. Animals were gently placed on the center of floor, and left to explore the arena for 5 min. The number of horizontal (crossings) and vertical (rearings) activity performed by each rat during the 5 min observation period was counted. The forced swimming test involves two individual exposures to a cylindrical tank with water in which rats cannot touch the bottom of the tank or escape. The tank is made of transparent Plexiglas, 50 cm tall, 20 cm in diameter, and filled with water ( 23-25°C ) to a depth of 20 cm. Water in the tank was changed after each rat. For the first exposure, rats without drug treatment were placed in the water for 15 min ( pre-test session ). Twenty-four hours later, rats were placed in the water again for a 5 min session ( test session ), and the immobility time of rats were recorded in seconds. Rats were treated with ketamine, propofol + ketamine, imipramine or saline only 60 min before the second exposure to the cylindrical tank of water ( test session ). Immediately after the forced swimming test, acutely saline, ketamine, propofol + ketamine, imipramine -treated rats were sacrificed and the skulls were removed and hippocampus was dissected and stored at -20℃for biochemical analyses. The BDNF protein levels in hippocampus were measured by anti-BDNF sandwich-ELISA . Results:①Open-field test: In this test, the treatment with ketamine,propofol+ketamine and imiprimine did not modify the number of crossings and rearings compared with saline treated-rats ( n=6, P>0.05);②Forced swimming test:The immobility time in group A, B, C, D, E, F, G was (132.67±5.13), (68.17±6.05),(97.33±10.88),(126.50±4.09), (124.83±7.65), (54.67±8.29) and (55.83±6.11) s, respectively. The immobility time in group B, C, F, G was lower than that in group A ( n=6, P<0.01); Compared with group C,the immobility time in group B, F, G was decreased ( n=6, P<0.01); The immobility time in group F, G was also lower than that in group B ( n=6, P<0.01).③The BDNF protein levels in hippocampus measured by anti-BDNF sandwich-ELISA: the BDNF levels in hippocampus in group A, B, C, D, E, F, G was (84.50±4.85), (118.33±4.68), (89.67±4.68), (80.17±4.49), (79.17±4.36), (115.00±6.20) and (113.67±5.89) pg/ml, respectively. the BDNF levels in hippocampus in group B, F, G was higher than that in group A (n=6, P<0.05), but had no differences among group B, F, G (n=6, P>0.05). Conclusions: Propofol could increase the antidepressant-like effects induced by acute administration of ketamine in rats, but the mechanism might not be not related to the BDNF levels in hippocampus.
引文
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