Melamine导致大鼠认知损伤的机制研究和VC与VE联用的可能治疗
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摘要
Melamine(1,3,5-三嗪-2,4,6-三胺),是一种重要的化工原料,常被用来生产三聚氰胺树脂与甲醛反应,用于生产塑料、粘合剂和面料等。尽管在很长一段时间内,三聚氰胺被准许可参与食品接触产品(如食品包装材料和餐具)的生产过程,但它不是食品添加剂,更没有允许直接添加到食品中。
Melamine的毒理学研究起始于1984年。然而,当时melamine的潜在毒性并没有引起公众的关注。大量的实验结果表明,婴儿或动物食用含melamine的食品后会导致严重的损伤,其中肾脏是其作用的主要靶器官。本实验室以前的研究表明,melamine可能损害海马锥体神经元功能和诱导神经细胞凋亡,并在细胞学实验中发现其氧化损伤作用。显然,melamine诱发的肾毒性并不能完全解释其神经毒性效应。
另一方面,melamine引发的毒性报道逐渐减少。但仍然未知服用melamine后是否会影响婴幼儿的中枢发育,甚至其毒性是否会影响成年后的认知等。抗氧化剂能够减少氧化应激,并缓解中枢神经系统功能的影响。维生素C和维生素E是两种重要的营养物质。它们能及时分解自由基,抵御异常增加的自由基的攻击,保护细胞正常的内环境稳态。联合使用维生素C和E能缓解阿尔兹海默症、帕金森症、肌萎缩性脊髓侧索硬化症以及共济运动失调等诱发的氧化损伤、焦虑和认知行为缺陷等,提高日常生活质量。
基于以上研究背景,本实验主要探讨慢性口服melamine对空间认知和海马突触可塑性的影响。同时,检测海马内自由基和抗氧化酶活性的变化。最后,通过服用抗氧化维生素C和E对melamine引起的氧化损伤进行恢复性治疗,并探讨其可能机制。
第一部分Melamine对空间认知和海马突触可塑性的影响
目的：探讨melamine对Wistar大鼠的空间认知能力和海马突触可塑性的影响,并进一步揭示其可能的生理机制。
材料与方法：大鼠随机分成两组：正常对照组(n=16)和Melamine (n=16)组。采用口服方式给予大鼠melamine悬浊液,每日一次。28天后,进行Morris水迷宫实验检测melamine对大鼠的空间认知能力的影响,包括学习、记忆和再获取能力。记录大鼠海马Schaffer侧枝到CA1区的突触传递可塑性变化,包括LTP和LTD。采用酶标法检测口服：melamine后大鼠海马内melamine含量变化。
结果：
1、ELISA检测结果显示：大鼠口服melamine28天后,海马内melamine含量异常增加,说明melamine能够通过血脑屏障,并在海马内积累。
2、Morris水迷宫实验显示：在学习和再获取学习阶段,melamine损伤大鼠逃避潜伏期明显增加；在空间探索阶段,目标象限停留时间比率和穿越目标平台次数也明显减少。说明慢性口服melamine能损伤大鼠空间认知能力,包括学习,参考记忆和再获取能力。
3、电生理记录实验结果显示：服用melamine后,LTP实验记录的场电位斜率明显低于正常组；而LTD实验记录的场电位斜率明显高于正常组。实验结果表明长期口服melamine会导致大鼠海马突触可塑性的损伤。
结论：melamine能够通过血脑屏障进入大脑,并在海马脑区积累。Melamine导致海马长时程突触可塑性损伤,最终导致认知能力,特别是认知弹性损伤。
第二部分Melamine导致大鼠空间认知损伤与诱发海马氧化应激相关
目的：为证实melamine导致空间认知损伤是否与破坏海马内氧化与抗氧化稳态相关。
方法：大鼠分为正常对照组(n=8)和Melamine (n=8)组。采用口服方式给予大鼠melamine悬浊液,每日一次。28天之后,进行Morris水迷宫实验检测了melamine对空间认知能力的影响以及海马内自由基、MDA、SOD和ATP水平。
结果：
1、慢性口服]melamine4周中,大鼠体重增加量明显减少。同时,海马内melamine浓度异常增加。
2、水迷宫实验结果表示：在学习阶段,melamine损伤大鼠逃避潜伏期明显延长,在空间记忆阶段,其目标象限停留百分比和目标平台穿越次数均明显减少。
3、组织学HE染色结果表明：melamine导致海马神经元染色明显加深,细胞核固缩,细胞松散,细胞质减少,出现大量坏死现象。
4、生化检测试验表明：慢性口服melamine会增加海马内自由基、MDA和ATP含量,同时降低抗氧化酶活性,如SOD和GSH-Px。
结论：Melamine在海马的神经毒性与氧化应激有关。
第三部分VC与VE联合对melamine导致的PC12细胞氧化应激的恢复作用
目的：探讨单独使用VC、VE或联合使用vitamin对melamine在PC12细胞引起的氧化应激的恢复作用。
方法：利用PC12细胞建立离体melamine损伤模型。MTT法检测细胞存活率。流式细胞计数法检测PC12细胞凋亡和胞内自由基数目。通过Hoechst33342染色观察细胞凋亡形态学变化。生化检测抗氧化酶系统在恢复前后的改变。
结果：
1、Melamine损伤后,单独使用VC、VE或联合使用vitamin均能一定程度上恢复细胞存活率,但联合使用维生素更具有优势。
2、联合维生素能有效地减少自由基的异常积累,降低MDA水平,帮恢复抗氧化酶活性,如SOD, CAT和GSH-Px。
3、Hoechst33342染色和流式细胞计数法结果显示：melamine能明显诱发细胞凋亡,并且联合vitamin能有效减少凋亡细胞数目。
4、联合使用vitamin通过抑制caspase-3活性抑制细胞凋亡的发生。结论：联合VC和VE能有效降低melamine诱发的氧化损伤,并抑制细胞凋亡。
第四部分VC与VE联用对melamine诱发的认知损伤的保护作用及机制研究
目的：探讨联合使用VC和VE对melamine损伤大鼠认知功能的恢复作用及其机制,包括氧化损伤和海马突触可塑性。
材料与方法：三周雄性大鼠随机分成四组：正常对照组(n=16),melamine(n=16), melamine+vitamin组(n=16)和vitamin组(n=16)。采用口服方式给予melamine悬浊液,每日一次,建立melamine损伤动物模型。随后,给予一周联合维生素C和E,腹腔注射每日一次。Morris水迷宫实验检测了大鼠空间认知能力变化。组织学HE染色观察海马锥体神经元形态变化。记录大鼠海马Schaffer侧枝到CA1区的突触可塑性变化,包括LTP和LTD。采用酶标法检测大鼠海马内自由基、MDA、NO和抗氧化剂和凋亡相关酶活性的变化等。
结果：
1、联合使用VC和VE能恢复大鼠空间认知损伤,包括能有效的改善学习和参考记忆能力,并一定程度上缓解再学习能力。
2、组织学观察发现：联合vitamin能有效减少melamine导致的细胞坏死等损伤。
3、电生理实验结果显示：melamine会导致大鼠海马突触长时程可塑性的损伤。联合使用viatamin能缓解海马突触可塑性损伤,包括LTP和LTD。
4、Melamine损伤大鼠注射VC和VE后,海马中自由基、MDA和NO含量恢复到正常水平。SOD、CAT、GSH-Px和NOS的活性也明显提高。神经元凋亡相关蛋白Bcl-2和caspase-3的活性也明显提高。
结论：联合VC和VE通过干预氧化损伤过程,降低melamine诱发的神经毒性,为治愈melamine导致的认知损伤提供了新的可能依据。
第五部分慢性孕期酒精导致大鼠性别二态性的空间认知和突触可塑性平衡损伤
目的：探讨孕期酒精性别二态性的认知行为变化,应用突触可塑性平衡探讨空间认知损伤的机制。
材料与方法：母鼠在妊娠期口服酒精并选取其雌雄后代进行实验。出生后36天后代大鼠进行MWM实验来检测其空间认知功能变化,记录其海马Schaffer侧枝到CA1区的突触可塑性变化。用方向指数衡量雌雄大鼠突触可塑性平衡的差异,进一步揭示其性别二态性。
结果：
1、CPEE使后代大鼠体重增加明显减少,同时导致头小畸形和海马重量减轻。
2、Morris水迷宫实验显示：CPEE后代大鼠的逃避潜伏期明显增加,并且其趋壁性明显增多。在探索阶段,CPEE后代大鼠在目标象限停留时间百分比和目标平台穿越次数均明显减少。此外,雌性后代比雄性后代认知损伤更严重。
3、电生理实验结果显示：CPEE导致雄性后代LTP明显降低而去增益明显增强；而雌性LTP明显增强而去增益明显减弱。此外,雌性后代的损伤程度更严重。
4、方向指数进一步揭示较雄性大鼠,雌性后代突触可塑性平衡损伤更为严重。
结论：CPEE导致认知和可塑性平衡性别二态性,并且突触可塑性平衡为CPEE引起的中枢功能紊乱提供了新的解释。
Melamine (1,3,5-Triazine-2,4,6-triamine), a synthetic chemical compound, is often used to produce melamine resin by reacting with formaldehyde. They have been used to manufacture plastics, adhesives and fabrics. Although melamine has been permitted to be used in some food contact products (e.g. food package materials and tableware) for a quite long time, it is not a kind of food additive and is never approved to be added to food directly.
The study of melamine toxicity in animals started as early as1984, however, it did not attract widespread public concern. Ample evidence certified that infants and animals were affected by food which were contaminated by melamine, and the renal pathology was the main manifestation in intoxicated case. Our previous studies showed that melamine produced the impairment of hippocampal function and induced apoptosis and oxidative damage in PC12cell. Obviously, the known nephrotoxicity of melamine could not fully explain its neurotoxicity effects.
On the other hand, its impact may persist longer than we thought. Antioxidants have been shown to decrease some of the biochemical measures of oxidative stress, and then mitigate function impairment of CNS. Vitamin C and E are two essential nutrients that can scavenge free radicals and constitute a strong line of defense in retarding reactive oxygen species (ROS)-induced cellular damage. Combination of vitamin C and E treatment can significantly attenuate oxidative damage, anxiety disorders and cognitive-behavioral impairment in AD, PD, amyotrophic lateral sclerosis and ataxia and improve their daily life viability as well as social activity.
Against above background, we investigated the effects of melamine on the spatial cognition and hippocampal synaptic plasticity of Wistar rats by gavage for28consecutive days. Meanwhile, hippocampal ROS and antioxidative enzyme activities were detected. Subsequently, we explored the antioxidative effect of vitamin C and E combination on melamine-induced neurotoxicology and attempted to make clear the potential mechanism.
Part1the effects of melamine on the spatial cognition and hippocampal synaptic plasticity in rats
Objective:To investigate the effects of melamine on spatial cognition and hippocampal synaptic plasticity in Wistar rats, and explore the potential mechanism.
Methods:Male adolescent Wistar rats, three-week-old, were randomly divided into two groups:control group (n=16) and melamine group (n=16). Rats were intragastric administered with melamine at a dose of300mg/kg/day once a day for4weeks. After that, Morris water maze (MWM) test was performed to evaluate the spatial cognitive function, including learning, reference memory and re-acquisition abilities. The long term potentiation (LTP) and long-term depression (LTD) from Schaffer collaterals to hippocampal CA1region were measured. In addition, the melamine concentration in the hippocampus was detected by enzyme linked immunosorbent assay (ELISA) method.
Results:
1. The ELISA test showed that the melamine content in the hippocampus was abnormally increased after melamine-treatment for28days, which indicated that melamine could pass through blood brain barrier (BBB).
2. The MWM test showed that the escape latencies in both initial training (IT) and reversal training (RT) stages were significantly increased in melamine group compared to that in control group (P<0.01). In space exploring test (SET) stage, both the platform crossings (P<0.01) and the quadrant dwell time (P<0.01) were decreased in melamine group compared to that in control group.
3. LTP recording were showed that the slope of field excitatory postsynaptic potentials (fEPSPs) was significantly lower in melamine group than that of control group (P<0.01). Meanwhile, LTD test was found that the fEPSPs slope was dramatically higher in melamine group than that in control group (P<0.01).
Conclusions:
Melamine is able to pass the BBB and accumulate in the hippocampus region. Meanwhile, the deleterious effects of melamine on hippocampal long-term synaptic plasticity broke the balance between stability and flexibility of cognition, which could further explain the poor performance in behavioral tests.
Part2Spatial cognition was impaired by melamine associated with oxidative damage in rat
Objective:To investigate whether cognitive deficits induced by melamine was associated with the impairment of oxidation-antioxidation homeostasis.
Methods:Male adolescent Wistar rats, three-week-old, were randomly divided into two groups:control group (n=8) and melamine group (n=8). Rats were intragastric administered with melamine at a dose of300mg/kg/day once a day for4weeks. After that, the MWM experiment and histopathological examination were performed. Meanwhile, the level of reactive oxygen species (ROS), malonaldehyde (MDA) superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and adenosine-triphosphate (ATP) levels were detected in the hippocampus.
Results:
1. During the four weeks of melamine treatment, rats gained significant less weight in melamine group than those in control group (P<0.01). There was an abnormal increasing in the concentration of melamine in hippocampus in melamine group.
2. In IT stage of MWM test, it was significantly prolonged in melamine group compared to that in control group (P<0.01). Furthermore, in SET stage, it was found that both the platform crossings (P<0.01) and the quadrant dwell time (P<0.01) were decreased in melamine group compared to that in control group. However, swimming speeds of these two groups remained constant throughout testing and no difference was found between them (P>0.05).
3. Results of biochemical tests:Chronic melamine exposure induced dysfunction of oxidation-antioxidation homeostasis, including increased the levels of ROS and MDA, decreased SOD, GSH-Px and ATP.
Conclusions:
The neurotoxicity of melamine in hippocampus may be partly associated with oxidative damage.
Part3The reversal effects of VC and VE joining application on hippocampal oxidative stress induced by melamine in PC12cells
Objective:To explore the potential treatment efficacy of vitamin C and vitamin E alone, the combination of vitamin C and E on oxidative stress induced by melamine.
Methods:PC12cells were cultured with melamine to establish an in vitro model of neuronal cells. The cellular viability was tested by MTT assay. The flow cytometry was used to detect the apoptosis of PC12cells and the level of intracellular reactive oxygen species (ROS). Furthermore, the inverted phase contrast microscope was used to observe the morphology of cells by Hoechst33342staining. The biochemical assays were used to evoluate the effect of antioxidative vitamins on the neurotoxicology of melamine.
Results:
1. Compared with vitamin C and vitamin E alone, the combination of vitamin C and E was statistically increased PC12cells viability as demonstrated by MTT assay.
2. The further evidences indicated that vitamin complex was effectively reduced the formation of reaction oxygen species ROS), decreased the level of MDA and elevated the activities of antioxidative enzymes, such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px).
3. Hoechst33342staining and flow cytometric analysis of apoptosis revealed the apoptotic nuclear features of the melamine-induced cell death, and showed that vitamin combination, but not vitamin C or vitamin E, effectively prevented PC12cells from this melamine-induced apoptosis.
4. The combination of vitamins effectively inhibited apoptosis via blocking the incesased activation of caspase-3.
Conclusions:
Vitamin E and C combination protect PC12cells from the injury induced by melamine through the down-regulation of oxidative stress and prevention of melamine-induced apoptosis.
Part4The potential treatment effects of VC and VE joining application on spatial cognition and its possible mechanisms in melamine-treated rats
Objective:To investigate the antioxidative effect of combination of vitamin C and E on cognitive function in melamine rats and explore the potential mechanism.
Methods:Male adolescent Wistar rats, three-week-old, were randomly divided into four groups:control group (n=16), melamine group (n=16), melamine+vtamin group (n=16) and vitamin group (n=16). Rats were intragastric administered with melamine at a dose of300mg/kg/day once a day for4weeks. Rat in melamine+vitamin group received vitamins C and E at a dose of150and200mg/kg respectively, intraperitoneally once a day for the next7consecutive days. After that, spatial cognitive function was investigated using a spatial version of the Morris water maze test. The long term potentiation (LTP) and long-term depression (LTD) from Schaffer collaterals to hippocampal CA1region were recorded. In addition, the levels of ROS, MDA and NO and the activities of SOD, CAT, GSH-Px, NOS, apoptotic related proteins Bcl-2and caspase-3were detected by ELISA method.
Results:
1. Rats treated with vitamins E and C had part of the above effects prevented in MWM tests, with mitigating the melamine-induced deficit in the learning and memory stage of MWM test but slightly improving the reversal learning ability.
2. Histological observation indicated that vitamin complex effectively alleviated the injuries of hippocampal neurons induced by melamine.
3. In vivo electrophysiological assessment found that melamine was able to cause the impairment of hippocampal synaptic plasticity drastically. The vitamins C plus E regimen mitigated the melamine-induced impairment of hippocampal synaptic plasticity, with an entirely ameliorated LTP and a significantly reversal LTD. Furthermore, in the S group, this vitamin regimen did not produce obviously deficits in behavioral and electrophysiological experiments.
4. ROS, MDA, NO contents were reversed to control levels after treatment with combination of vitamin C and E. SOD, CAT, GSH-Px, NOS activities were also improved compared to melamine-treated group. The neural apoptosis in the hippocampus were ameliorated by regulating the expression of pro-apoptotic protein (Bcl-2) and anti-apoptotic protein (caspase-3).
Conclusions:
It is concluded that oxidative damage plays an important role in the melamine-induced hippocampal impairment. The modulation of oxidative stress with vitamins E and C reduced the melamine-induced damage and may support to a novel therapeutic strategy to the cognitive dysfunction observed in melamine-induced patient.
Part5Spatial cognition and sexually dimorphic synaptic plasticity balance impairment in rats with chronic prenatal ethanol exposure
Objective:To investigate the sexual different effects of chronic prenatal ethanol exposure (CPEE) on behavior cognition and cognitive flexibility, and interpret the possible mechanism by evaluating the alternation of synaptic plasticity balance.
Methods:The animal model was produced by ethanol exposure throughout gestational period with4g/kg bodyweight. The offspring of both male and female was selected and studied on postnatal days36. After that, the Morris water maze (MWM) test was performed to evaluate the spatial cognitive function, including learning, reference memory and re-acquisition abilities. LTP and depotentiation from Schaffer collaterals to hippocampal CA1region were recorded.
Results:
1. It demonstrated that chronic ethanol exposure reduced birth weight, losing bodyweight gain, microcephaly and retarded hippocampal weight.
2. In Morris water maze (MWM) test, it was found that the latencies were significantly higher in adolescent CPEE-treated rats than that in normal rats. The time spent of CPEE-treated rats was markedly increased near the periphery of the pool. Furthermore, they took less time in the target quadrant and reduced platform crossing times in the probe phase.In addition, the behavioral test also showed that there was a particularly serious impairment of females than that of males after CPEE treatment.
3. Electrophysiological studies showed that CPEE dramatically depressed long-term potentiation (LTP) and obviously enhanced depotentiation in male adolescent hippocampus, while drastically exaggerated LTP and hardly impacted depotentiation in female.
4. Our original index also displayed that synaptic plasticity balance of female was much more sensitive to the effect of CPEE than that of males.
Conclusions:
The investigation revealed the sex different effect of CPEE on synaptic plasticity balance and provided a better understanding of CNS dysfunction in CPEE treatment.
Melamine的毒理学研究起始于1984年。然而,当时melamine的潜在毒性并没有引起公众的关注。大量的实验结果表明,婴儿或动物食用含melamine的食品后会导致严重的损伤,其中肾脏是其作用的主要靶器官。本实验室以前的研究表明,melamine可能损害海马锥体神经元功能和诱导神经细胞凋亡,并在细胞学实验中发现其氧化损伤作用。显然,melamine诱发的肾毒性并不能完全解释其神经毒性效应。
另一方面,melamine引发的毒性报道逐渐减少。但仍然未知服用melamine后是否会影响婴幼儿的中枢发育,甚至其毒性是否会影响成年后的认知等。抗氧化剂能够减少氧化应激,并缓解中枢神经系统功能的影响。维生素C和维生素E是两种重要的营养物质。它们能及时分解自由基,抵御异常增加的自由基的攻击,保护细胞正常的内环境稳态。联合使用维生素C和E能缓解阿尔兹海默症、帕金森症、肌萎缩性脊髓侧索硬化症以及共济运动失调等诱发的氧化损伤、焦虑和认知行为缺陷等,提高日常生活质量。
基于以上研究背景,本实验主要探讨慢性口服melamine对空间认知和海马突触可塑性的影响。同时,检测海马内自由基和抗氧化酶活性的变化。最后,通过服用抗氧化维生素C和E对melamine引起的氧化损伤进行恢复性治疗,并探讨其可能机制。
第一部分Melamine对空间认知和海马突触可塑性的影响
目的：探讨melamine对Wistar大鼠的空间认知能力和海马突触可塑性的影响,并进一步揭示其可能的生理机制。
材料与方法：大鼠随机分成两组：正常对照组(n=16)和Melamine (n=16)组。采用口服方式给予大鼠melamine悬浊液,每日一次。28天后,进行Morris水迷宫实验检测melamine对大鼠的空间认知能力的影响,包括学习、记忆和再获取能力。记录大鼠海马Schaffer侧枝到CA1区的突触传递可塑性变化,包括LTP和LTD。采用酶标法检测口服：melamine后大鼠海马内melamine含量变化。
结果：
1、ELISA检测结果显示：大鼠口服melamine28天后,海马内melamine含量异常增加,说明melamine能够通过血脑屏障,并在海马内积累。
2、Morris水迷宫实验显示：在学习和再获取学习阶段,melamine损伤大鼠逃避潜伏期明显增加；在空间探索阶段,目标象限停留时间比率和穿越目标平台次数也明显减少。说明慢性口服melamine能损伤大鼠空间认知能力,包括学习,参考记忆和再获取能力。
3、电生理记录实验结果显示：服用melamine后,LTP实验记录的场电位斜率明显低于正常组；而LTD实验记录的场电位斜率明显高于正常组。实验结果表明长期口服melamine会导致大鼠海马突触可塑性的损伤。
结论：melamine能够通过血脑屏障进入大脑,并在海马脑区积累。Melamine导致海马长时程突触可塑性损伤,最终导致认知能力,特别是认知弹性损伤。
第二部分Melamine导致大鼠空间认知损伤与诱发海马氧化应激相关
目的：为证实melamine导致空间认知损伤是否与破坏海马内氧化与抗氧化稳态相关。
方法：大鼠分为正常对照组(n=8)和Melamine (n=8)组。采用口服方式给予大鼠melamine悬浊液,每日一次。28天之后,进行Morris水迷宫实验检测了melamine对空间认知能力的影响以及海马内自由基、MDA、SOD和ATP水平。
结果：
1、慢性口服]melamine4周中,大鼠体重增加量明显减少。同时,海马内melamine浓度异常增加。
2、水迷宫实验结果表示：在学习阶段,melamine损伤大鼠逃避潜伏期明显延长,在空间记忆阶段,其目标象限停留百分比和目标平台穿越次数均明显减少。
3、组织学HE染色结果表明：melamine导致海马神经元染色明显加深,细胞核固缩,细胞松散,细胞质减少,出现大量坏死现象。
4、生化检测试验表明：慢性口服melamine会增加海马内自由基、MDA和ATP含量,同时降低抗氧化酶活性,如SOD和GSH-Px。
结论：Melamine在海马的神经毒性与氧化应激有关。
第三部分VC与VE联合对melamine导致的PC12细胞氧化应激的恢复作用
目的：探讨单独使用VC、VE或联合使用vitamin对melamine在PC12细胞引起的氧化应激的恢复作用。
方法：利用PC12细胞建立离体melamine损伤模型。MTT法检测细胞存活率。流式细胞计数法检测PC12细胞凋亡和胞内自由基数目。通过Hoechst33342染色观察细胞凋亡形态学变化。生化检测抗氧化酶系统在恢复前后的改变。
结果：
1、Melamine损伤后,单独使用VC、VE或联合使用vitamin均能一定程度上恢复细胞存活率,但联合使用维生素更具有优势。
2、联合维生素能有效地减少自由基的异常积累,降低MDA水平,帮恢复抗氧化酶活性,如SOD, CAT和GSH-Px。
3、Hoechst33342染色和流式细胞计数法结果显示：melamine能明显诱发细胞凋亡,并且联合vitamin能有效减少凋亡细胞数目。
4、联合使用vitamin通过抑制caspase-3活性抑制细胞凋亡的发生。结论：联合VC和VE能有效降低melamine诱发的氧化损伤,并抑制细胞凋亡。
第四部分VC与VE联用对melamine诱发的认知损伤的保护作用及机制研究
目的：探讨联合使用VC和VE对melamine损伤大鼠认知功能的恢复作用及其机制,包括氧化损伤和海马突触可塑性。
材料与方法：三周雄性大鼠随机分成四组：正常对照组(n=16),melamine(n=16), melamine+vitamin组(n=16)和vitamin组(n=16)。采用口服方式给予melamine悬浊液,每日一次,建立melamine损伤动物模型。随后,给予一周联合维生素C和E,腹腔注射每日一次。Morris水迷宫实验检测了大鼠空间认知能力变化。组织学HE染色观察海马锥体神经元形态变化。记录大鼠海马Schaffer侧枝到CA1区的突触可塑性变化,包括LTP和LTD。采用酶标法检测大鼠海马内自由基、MDA、NO和抗氧化剂和凋亡相关酶活性的变化等。
结果：
1、联合使用VC和VE能恢复大鼠空间认知损伤,包括能有效的改善学习和参考记忆能力,并一定程度上缓解再学习能力。
2、组织学观察发现：联合vitamin能有效减少melamine导致的细胞坏死等损伤。
3、电生理实验结果显示：melamine会导致大鼠海马突触长时程可塑性的损伤。联合使用viatamin能缓解海马突触可塑性损伤,包括LTP和LTD。
4、Melamine损伤大鼠注射VC和VE后,海马中自由基、MDA和NO含量恢复到正常水平。SOD、CAT、GSH-Px和NOS的活性也明显提高。神经元凋亡相关蛋白Bcl-2和caspase-3的活性也明显提高。
结论：联合VC和VE通过干预氧化损伤过程,降低melamine诱发的神经毒性,为治愈melamine导致的认知损伤提供了新的可能依据。
第五部分慢性孕期酒精导致大鼠性别二态性的空间认知和突触可塑性平衡损伤
目的：探讨孕期酒精性别二态性的认知行为变化,应用突触可塑性平衡探讨空间认知损伤的机制。
材料与方法：母鼠在妊娠期口服酒精并选取其雌雄后代进行实验。出生后36天后代大鼠进行MWM实验来检测其空间认知功能变化,记录其海马Schaffer侧枝到CA1区的突触可塑性变化。用方向指数衡量雌雄大鼠突触可塑性平衡的差异,进一步揭示其性别二态性。
结果：
1、CPEE使后代大鼠体重增加明显减少,同时导致头小畸形和海马重量减轻。
2、Morris水迷宫实验显示：CPEE后代大鼠的逃避潜伏期明显增加,并且其趋壁性明显增多。在探索阶段,CPEE后代大鼠在目标象限停留时间百分比和目标平台穿越次数均明显减少。此外,雌性后代比雄性后代认知损伤更严重。
3、电生理实验结果显示：CPEE导致雄性后代LTP明显降低而去增益明显增强；而雌性LTP明显增强而去增益明显减弱。此外,雌性后代的损伤程度更严重。
4、方向指数进一步揭示较雄性大鼠,雌性后代突触可塑性平衡损伤更为严重。
结论：CPEE导致认知和可塑性平衡性别二态性,并且突触可塑性平衡为CPEE引起的中枢功能紊乱提供了新的解释。
Melamine (1,3,5-Triazine-2,4,6-triamine), a synthetic chemical compound, is often used to produce melamine resin by reacting with formaldehyde. They have been used to manufacture plastics, adhesives and fabrics. Although melamine has been permitted to be used in some food contact products (e.g. food package materials and tableware) for a quite long time, it is not a kind of food additive and is never approved to be added to food directly.
The study of melamine toxicity in animals started as early as1984, however, it did not attract widespread public concern. Ample evidence certified that infants and animals were affected by food which were contaminated by melamine, and the renal pathology was the main manifestation in intoxicated case. Our previous studies showed that melamine produced the impairment of hippocampal function and induced apoptosis and oxidative damage in PC12cell. Obviously, the known nephrotoxicity of melamine could not fully explain its neurotoxicity effects.
On the other hand, its impact may persist longer than we thought. Antioxidants have been shown to decrease some of the biochemical measures of oxidative stress, and then mitigate function impairment of CNS. Vitamin C and E are two essential nutrients that can scavenge free radicals and constitute a strong line of defense in retarding reactive oxygen species (ROS)-induced cellular damage. Combination of vitamin C and E treatment can significantly attenuate oxidative damage, anxiety disorders and cognitive-behavioral impairment in AD, PD, amyotrophic lateral sclerosis and ataxia and improve their daily life viability as well as social activity.
Against above background, we investigated the effects of melamine on the spatial cognition and hippocampal synaptic plasticity of Wistar rats by gavage for28consecutive days. Meanwhile, hippocampal ROS and antioxidative enzyme activities were detected. Subsequently, we explored the antioxidative effect of vitamin C and E combination on melamine-induced neurotoxicology and attempted to make clear the potential mechanism.
Part1the effects of melamine on the spatial cognition and hippocampal synaptic plasticity in rats
Objective:To investigate the effects of melamine on spatial cognition and hippocampal synaptic plasticity in Wistar rats, and explore the potential mechanism.
Methods:Male adolescent Wistar rats, three-week-old, were randomly divided into two groups:control group (n=16) and melamine group (n=16). Rats were intragastric administered with melamine at a dose of300mg/kg/day once a day for4weeks. After that, Morris water maze (MWM) test was performed to evaluate the spatial cognitive function, including learning, reference memory and re-acquisition abilities. The long term potentiation (LTP) and long-term depression (LTD) from Schaffer collaterals to hippocampal CA1region were measured. In addition, the melamine concentration in the hippocampus was detected by enzyme linked immunosorbent assay (ELISA) method.
Results:
1. The ELISA test showed that the melamine content in the hippocampus was abnormally increased after melamine-treatment for28days, which indicated that melamine could pass through blood brain barrier (BBB).
2. The MWM test showed that the escape latencies in both initial training (IT) and reversal training (RT) stages were significantly increased in melamine group compared to that in control group (P<0.01). In space exploring test (SET) stage, both the platform crossings (P<0.01) and the quadrant dwell time (P<0.01) were decreased in melamine group compared to that in control group.
3. LTP recording were showed that the slope of field excitatory postsynaptic potentials (fEPSPs) was significantly lower in melamine group than that of control group (P<0.01). Meanwhile, LTD test was found that the fEPSPs slope was dramatically higher in melamine group than that in control group (P<0.01).
Conclusions:
Melamine is able to pass the BBB and accumulate in the hippocampus region. Meanwhile, the deleterious effects of melamine on hippocampal long-term synaptic plasticity broke the balance between stability and flexibility of cognition, which could further explain the poor performance in behavioral tests.
Part2Spatial cognition was impaired by melamine associated with oxidative damage in rat
Objective:To investigate whether cognitive deficits induced by melamine was associated with the impairment of oxidation-antioxidation homeostasis.
Methods:Male adolescent Wistar rats, three-week-old, were randomly divided into two groups:control group (n=8) and melamine group (n=8). Rats were intragastric administered with melamine at a dose of300mg/kg/day once a day for4weeks. After that, the MWM experiment and histopathological examination were performed. Meanwhile, the level of reactive oxygen species (ROS), malonaldehyde (MDA) superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and adenosine-triphosphate (ATP) levels were detected in the hippocampus.
Results:
1. During the four weeks of melamine treatment, rats gained significant less weight in melamine group than those in control group (P<0.01). There was an abnormal increasing in the concentration of melamine in hippocampus in melamine group.
2. In IT stage of MWM test, it was significantly prolonged in melamine group compared to that in control group (P<0.01). Furthermore, in SET stage, it was found that both the platform crossings (P<0.01) and the quadrant dwell time (P<0.01) were decreased in melamine group compared to that in control group. However, swimming speeds of these two groups remained constant throughout testing and no difference was found between them (P>0.05).
3. Results of biochemical tests:Chronic melamine exposure induced dysfunction of oxidation-antioxidation homeostasis, including increased the levels of ROS and MDA, decreased SOD, GSH-Px and ATP.
Conclusions:
The neurotoxicity of melamine in hippocampus may be partly associated with oxidative damage.
Part3The reversal effects of VC and VE joining application on hippocampal oxidative stress induced by melamine in PC12cells
Objective:To explore the potential treatment efficacy of vitamin C and vitamin E alone, the combination of vitamin C and E on oxidative stress induced by melamine.
Methods:PC12cells were cultured with melamine to establish an in vitro model of neuronal cells. The cellular viability was tested by MTT assay. The flow cytometry was used to detect the apoptosis of PC12cells and the level of intracellular reactive oxygen species (ROS). Furthermore, the inverted phase contrast microscope was used to observe the morphology of cells by Hoechst33342staining. The biochemical assays were used to evoluate the effect of antioxidative vitamins on the neurotoxicology of melamine.
Results:
1. Compared with vitamin C and vitamin E alone, the combination of vitamin C and E was statistically increased PC12cells viability as demonstrated by MTT assay.
2. The further evidences indicated that vitamin complex was effectively reduced the formation of reaction oxygen species ROS), decreased the level of MDA and elevated the activities of antioxidative enzymes, such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px).
3. Hoechst33342staining and flow cytometric analysis of apoptosis revealed the apoptotic nuclear features of the melamine-induced cell death, and showed that vitamin combination, but not vitamin C or vitamin E, effectively prevented PC12cells from this melamine-induced apoptosis.
4. The combination of vitamins effectively inhibited apoptosis via blocking the incesased activation of caspase-3.
Conclusions:
Vitamin E and C combination protect PC12cells from the injury induced by melamine through the down-regulation of oxidative stress and prevention of melamine-induced apoptosis.
Part4The potential treatment effects of VC and VE joining application on spatial cognition and its possible mechanisms in melamine-treated rats
Objective:To investigate the antioxidative effect of combination of vitamin C and E on cognitive function in melamine rats and explore the potential mechanism.
Methods:Male adolescent Wistar rats, three-week-old, were randomly divided into four groups:control group (n=16), melamine group (n=16), melamine+vtamin group (n=16) and vitamin group (n=16). Rats were intragastric administered with melamine at a dose of300mg/kg/day once a day for4weeks. Rat in melamine+vitamin group received vitamins C and E at a dose of150and200mg/kg respectively, intraperitoneally once a day for the next7consecutive days. After that, spatial cognitive function was investigated using a spatial version of the Morris water maze test. The long term potentiation (LTP) and long-term depression (LTD) from Schaffer collaterals to hippocampal CA1region were recorded. In addition, the levels of ROS, MDA and NO and the activities of SOD, CAT, GSH-Px, NOS, apoptotic related proteins Bcl-2and caspase-3were detected by ELISA method.
Results:
1. Rats treated with vitamins E and C had part of the above effects prevented in MWM tests, with mitigating the melamine-induced deficit in the learning and memory stage of MWM test but slightly improving the reversal learning ability.
2. Histological observation indicated that vitamin complex effectively alleviated the injuries of hippocampal neurons induced by melamine.
3. In vivo electrophysiological assessment found that melamine was able to cause the impairment of hippocampal synaptic plasticity drastically. The vitamins C plus E regimen mitigated the melamine-induced impairment of hippocampal synaptic plasticity, with an entirely ameliorated LTP and a significantly reversal LTD. Furthermore, in the S group, this vitamin regimen did not produce obviously deficits in behavioral and electrophysiological experiments.
4. ROS, MDA, NO contents were reversed to control levels after treatment with combination of vitamin C and E. SOD, CAT, GSH-Px, NOS activities were also improved compared to melamine-treated group. The neural apoptosis in the hippocampus were ameliorated by regulating the expression of pro-apoptotic protein (Bcl-2) and anti-apoptotic protein (caspase-3).
Conclusions:
It is concluded that oxidative damage plays an important role in the melamine-induced hippocampal impairment. The modulation of oxidative stress with vitamins E and C reduced the melamine-induced damage and may support to a novel therapeutic strategy to the cognitive dysfunction observed in melamine-induced patient.
Part5Spatial cognition and sexually dimorphic synaptic plasticity balance impairment in rats with chronic prenatal ethanol exposure
Objective:To investigate the sexual different effects of chronic prenatal ethanol exposure (CPEE) on behavior cognition and cognitive flexibility, and interpret the possible mechanism by evaluating the alternation of synaptic plasticity balance.
Methods:The animal model was produced by ethanol exposure throughout gestational period with4g/kg bodyweight. The offspring of both male and female was selected and studied on postnatal days36. After that, the Morris water maze (MWM) test was performed to evaluate the spatial cognitive function, including learning, reference memory and re-acquisition abilities. LTP and depotentiation from Schaffer collaterals to hippocampal CA1region were recorded.
Results:
1. It demonstrated that chronic ethanol exposure reduced birth weight, losing bodyweight gain, microcephaly and retarded hippocampal weight.
2. In Morris water maze (MWM) test, it was found that the latencies were significantly higher in adolescent CPEE-treated rats than that in normal rats. The time spent of CPEE-treated rats was markedly increased near the periphery of the pool. Furthermore, they took less time in the target quadrant and reduced platform crossing times in the probe phase.In addition, the behavioral test also showed that there was a particularly serious impairment of females than that of males after CPEE treatment.
3. Electrophysiological studies showed that CPEE dramatically depressed long-term potentiation (LTP) and obviously enhanced depotentiation in male adolescent hippocampus, while drastically exaggerated LTP and hardly impacted depotentiation in female.
4. Our original index also displayed that synaptic plasticity balance of female was much more sensitive to the effect of CPEE than that of males.
Conclusions:
The investigation revealed the sex different effect of CPEE on synaptic plasticity balance and provided a better understanding of CNS dysfunction in CPEE treatment.
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