24小时内MDMA对大鼠脑组织氧化应激、凋亡相关蛋白及内质网Ca~(2+)通道的影响
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摘要
[目的]
当前,MDMA在全世界泛滥流行,是法医学和毒理学研究的热点之一。目前有关MDMA的研究主要局限于24h以上的毒性作用机制,而人们对24h以内的MDMA如何影响人体知之甚少。由于服用MDMA最短可在几分钟内起效,对人体中枢神经系统产生影响,因此对24h内神经系统MDMA的作用机制的研究非常必要。本课题利用多种方法和技术,从氧化应激、细胞凋亡和内质网Ca2+通道等方面对MDMA染毒大鼠24h内脑组织进行研究,希望能进一步阐述MDMA中毒的特点及对机体的影响,为完善MDMA法医毒理学作用机制奠定理论基础。
[方法]
实验1：
1.建立腹腔注射MDMA(20mg/kg)成年SD大鼠染毒模型,实验组27只,对照组5只。拟将实验组按染毒后1h、12h和24h分组处死,每组9只。在处死1h组实验动物后,2-6h内有6只大鼠发生死亡,故将其分为自发死亡组,剩余12只实验动物随机分为12h处死组和24h处死组,每组6只,取脑组织备用；
2.用高效液相色谱法测定不同时间段各组脑组织内5-HT和DA含量；
3.用硫代巴比妥酸法和羟胺法分别测定不同组间SOD、MDA的活性；
实验2：
1.染毒步骤同实验1,动物及分组为实验1中的对照组、1h组、12h组和24h组。
2.用HE、TUNNEL及免疫组化的方法染各组脑组织切片,并用Western Blot方法测定各组Bcl-2、Bax及Caspase-3的含量；
实验3：
1.染毒及分组同实验2
2.用RT-PCR和免疫组化的方法测定Ryr2和SERCA2的表达情况。
[结果]
实验1：
1.染毒大鼠有明显的毒性反应,染毒后自发死亡的大鼠均在染毒6h内发生,死亡率为22.22%。
2.处死组与自发死亡组大鼠脑组织5-HT均较对照组降低,1h组与12h组DA与对照组无统计学差异,24h组和死亡组比对照著升高。
3.1h组、24h组SOD高于对照组,12h组与对照组无统计学差异；死亡组低于对照组。
实验2：
1. TUNNEL染色各实验组与对照组无显著性差异。
2.各实验组大鼠脑组织Bcl-2/Bax均高于对照组。
3.各实验组大鼠脑组织Caspase-3均低于对照组。
实验3：
1.Ryr2的RT-PCR和免疫组化的结果均是1h组与对照组无统计学差异,12h组和24h组均高于对照组,随时间的延长,呈逐渐上升的趋势。
2. SERCA2的RT-PCR和免疫组化结果均是1h组、12h组和24h组高于对照组,随时间的延长,呈逐渐上升的趋势。
[结论]
1.MDMA染毒24h内,可诱发脑组织抗氧化物质SOD的生成及脑组织的抗凋亡效应。
2. MDMA染毒24h内,可诱发内质网Ca2+通道蛋白Ryr2和SERCA2的表达。
3.MDMA染毒24h内对脑组织有一定的保护作用,这种保护作用与抗氧化酶SOD、抗凋亡蛋白Bcl-2和内质网Ca2+通道蛋白的表达有关,且随着时间的延长,其保护作用有下降的趋势。
4.急性MDMA中毒死亡的大鼠,单胺类神经元损伤及氧化应激反应严重,其死亡机制可能与之有关。
[Objectives]
3,4-Methylenedioxymethamphetamine (MDMA, also known as "ecstasy") is a ring-substituted phenylamine with very high abuse liability around the world. Many medico legists and toxicologists made researches on its mechanism of the toxicity. However, almost all of these studies were focus on the causes of the changes after abuse of MDMA24hours later. Whether does abuse of MDMA have any effects on organism within the first day? Little is understood about it. Some preclinical and clinical evidences show MDMA can made some users excited and leads to neurotoxic effects on central neurons only within a few minutes. For this reason, it is very necessary to study the changes on central nervous system for the first24hours after the consumption of MDMA. In order to find out the nervous effects within the first24hours, the subject made research on three probable aspects (oxidative stress, apoptosis and endoplasmic reticulum Ca2+channel) on brain tissue in rats.
[Methods] Part1:
1. An experiment model of forensic toxicology was set up under in vivo adult animal conditions, for administration of MDMA20mg/kg into abdominal cavity.32SD rats were supposed to be divided into experimental group(27rats) and control group(5rats). Then, all the rats in experimental group were consumed to be killed in three groups:1h,12h and24h after using MDMA.9rats in the1h group were executed. However,6rats died spontaneously during2-6h after injection of MDMA, which was named as spontaneous death group. The remaining rats were randomly divided into12h group(6rats) and24h group(6rats). The brain tissues of each group rats were taken out to reserve.
2. To analyze of5-HT and DA in three groups and spontaneous death group by High Performance Liquid Chromatography (HPLC).
3. To measure the activity of MDA in different groups by the method of TBA; to measure the activity of SOD by Hydroxylamine method. Part2:
1.1h group,12h group,24h group and contral group are the same as the part1.
2. To present rats' brain cells by HE and TUNNEL staining; to analyze of the proteins about apoptosis:bcl-2, bax and caspase-3by Western Blot and immumohistochemical staining. Part3:
1. To administration of drugs and to make groups as same as the part2.
2. To analyze the expression of Ryr2and SERCA2by the method of RT-PCR and immumohistochemical staining.
[Results] Part1:
1. Obvious toxic reactions were observed after administration of MDMA, and there was spontaneous death of rats in6hours with the mortality rate was22.22%.
2. MDMA administration produced significant decreases in only5-HT tissue content in each group, while there were significant grows in DA content in both24h group and spontaneous death group.
3. There were increases of SOD in1h and24h group comparing to the control group, while decline in spontaneous death group. Part2:
There was no significant difference in the number of apoptotic cells in each exposed group, while MDMA administration led to the bcl-2/bax ratio rising and caspase-3falling. Part3:
1. The analysis of Ryr2was1h group had no obvious change, but the contents in12h and24h groups increased significantly after MDMA abusing.
2. The expression of SERCA2was higher in exposed groups than control group.
3. The contents about expression and mRNA of Ryr2and SERCA2were increasing with time.
[Conclusions]
1. Disposable20mg/kg MDMA administration in rats can lead to the neurotoxicity on monoamine terminals and oxidative stress reaction in brain within24hours. Serious damages caused by MDMA maybe fatal.
2. MDMA administration produces the raising of antioxidative enzymes SOD and the effect of resistance to apoptosis.
3. MDMA administration can induce the expression of Ryr2and SERCA2who are endoplasmic reticulum Ca2+channel proteins.
4. Sublethal injury by MDMA can provide some protections on brain tissue. The mechanism of nervous protections is related with antioxidative enzymes SOD, anti-apoptotic protein Bcl-2and endoplasmic reticulum of Ca2+channel proteins.
当前,MDMA在全世界泛滥流行,是法医学和毒理学研究的热点之一。目前有关MDMA的研究主要局限于24h以上的毒性作用机制,而人们对24h以内的MDMA如何影响人体知之甚少。由于服用MDMA最短可在几分钟内起效,对人体中枢神经系统产生影响,因此对24h内神经系统MDMA的作用机制的研究非常必要。本课题利用多种方法和技术,从氧化应激、细胞凋亡和内质网Ca2+通道等方面对MDMA染毒大鼠24h内脑组织进行研究,希望能进一步阐述MDMA中毒的特点及对机体的影响,为完善MDMA法医毒理学作用机制奠定理论基础。
[方法]
实验1：
1.建立腹腔注射MDMA(20mg/kg)成年SD大鼠染毒模型,实验组27只,对照组5只。拟将实验组按染毒后1h、12h和24h分组处死,每组9只。在处死1h组实验动物后,2-6h内有6只大鼠发生死亡,故将其分为自发死亡组,剩余12只实验动物随机分为12h处死组和24h处死组,每组6只,取脑组织备用；
2.用高效液相色谱法测定不同时间段各组脑组织内5-HT和DA含量；
3.用硫代巴比妥酸法和羟胺法分别测定不同组间SOD、MDA的活性；
实验2：
1.染毒步骤同实验1,动物及分组为实验1中的对照组、1h组、12h组和24h组。
2.用HE、TUNNEL及免疫组化的方法染各组脑组织切片,并用Western Blot方法测定各组Bcl-2、Bax及Caspase-3的含量；
实验3：
1.染毒及分组同实验2
2.用RT-PCR和免疫组化的方法测定Ryr2和SERCA2的表达情况。
[结果]
实验1：
1.染毒大鼠有明显的毒性反应,染毒后自发死亡的大鼠均在染毒6h内发生,死亡率为22.22%。
2.处死组与自发死亡组大鼠脑组织5-HT均较对照组降低,1h组与12h组DA与对照组无统计学差异,24h组和死亡组比对照著升高。
3.1h组、24h组SOD高于对照组,12h组与对照组无统计学差异；死亡组低于对照组。
实验2：
1. TUNNEL染色各实验组与对照组无显著性差异。
2.各实验组大鼠脑组织Bcl-2/Bax均高于对照组。
3.各实验组大鼠脑组织Caspase-3均低于对照组。
实验3：
1.Ryr2的RT-PCR和免疫组化的结果均是1h组与对照组无统计学差异,12h组和24h组均高于对照组,随时间的延长,呈逐渐上升的趋势。
2. SERCA2的RT-PCR和免疫组化结果均是1h组、12h组和24h组高于对照组,随时间的延长,呈逐渐上升的趋势。
[结论]
1.MDMA染毒24h内,可诱发脑组织抗氧化物质SOD的生成及脑组织的抗凋亡效应。
2. MDMA染毒24h内,可诱发内质网Ca2+通道蛋白Ryr2和SERCA2的表达。
3.MDMA染毒24h内对脑组织有一定的保护作用,这种保护作用与抗氧化酶SOD、抗凋亡蛋白Bcl-2和内质网Ca2+通道蛋白的表达有关,且随着时间的延长,其保护作用有下降的趋势。
4.急性MDMA中毒死亡的大鼠,单胺类神经元损伤及氧化应激反应严重,其死亡机制可能与之有关。
[Objectives]
3,4-Methylenedioxymethamphetamine (MDMA, also known as "ecstasy") is a ring-substituted phenylamine with very high abuse liability around the world. Many medico legists and toxicologists made researches on its mechanism of the toxicity. However, almost all of these studies were focus on the causes of the changes after abuse of MDMA24hours later. Whether does abuse of MDMA have any effects on organism within the first day? Little is understood about it. Some preclinical and clinical evidences show MDMA can made some users excited and leads to neurotoxic effects on central neurons only within a few minutes. For this reason, it is very necessary to study the changes on central nervous system for the first24hours after the consumption of MDMA. In order to find out the nervous effects within the first24hours, the subject made research on three probable aspects (oxidative stress, apoptosis and endoplasmic reticulum Ca2+channel) on brain tissue in rats.
[Methods] Part1:
1. An experiment model of forensic toxicology was set up under in vivo adult animal conditions, for administration of MDMA20mg/kg into abdominal cavity.32SD rats were supposed to be divided into experimental group(27rats) and control group(5rats). Then, all the rats in experimental group were consumed to be killed in three groups:1h,12h and24h after using MDMA.9rats in the1h group were executed. However,6rats died spontaneously during2-6h after injection of MDMA, which was named as spontaneous death group. The remaining rats were randomly divided into12h group(6rats) and24h group(6rats). The brain tissues of each group rats were taken out to reserve.
2. To analyze of5-HT and DA in three groups and spontaneous death group by High Performance Liquid Chromatography (HPLC).
3. To measure the activity of MDA in different groups by the method of TBA; to measure the activity of SOD by Hydroxylamine method. Part2:
1.1h group,12h group,24h group and contral group are the same as the part1.
2. To present rats' brain cells by HE and TUNNEL staining; to analyze of the proteins about apoptosis:bcl-2, bax and caspase-3by Western Blot and immumohistochemical staining. Part3:
1. To administration of drugs and to make groups as same as the part2.
2. To analyze the expression of Ryr2and SERCA2by the method of RT-PCR and immumohistochemical staining.
[Results] Part1:
1. Obvious toxic reactions were observed after administration of MDMA, and there was spontaneous death of rats in6hours with the mortality rate was22.22%.
2. MDMA administration produced significant decreases in only5-HT tissue content in each group, while there were significant grows in DA content in both24h group and spontaneous death group.
3. There were increases of SOD in1h and24h group comparing to the control group, while decline in spontaneous death group. Part2:
There was no significant difference in the number of apoptotic cells in each exposed group, while MDMA administration led to the bcl-2/bax ratio rising and caspase-3falling. Part3:
1. The analysis of Ryr2was1h group had no obvious change, but the contents in12h and24h groups increased significantly after MDMA abusing.
2. The expression of SERCA2was higher in exposed groups than control group.
3. The contents about expression and mRNA of Ryr2and SERCA2were increasing with time.
[Conclusions]
1. Disposable20mg/kg MDMA administration in rats can lead to the neurotoxicity on monoamine terminals and oxidative stress reaction in brain within24hours. Serious damages caused by MDMA maybe fatal.
2. MDMA administration produces the raising of antioxidative enzymes SOD and the effect of resistance to apoptosis.
3. MDMA administration can induce the expression of Ryr2and SERCA2who are endoplasmic reticulum Ca2+channel proteins.
4. Sublethal injury by MDMA can provide some protections on brain tissue. The mechanism of nervous protections is related with antioxidative enzymes SOD, anti-apoptotic protein Bcl-2and endoplasmic reticulum of Ca2+channel proteins.
引文
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