低浓度吗啡抗帕金森病分子机制的研究
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摘要
帕金森病(Parkinson Disease, PD)是一种常见的神经退行性疾病。它的主要临床表现为肌肉强直、运动减少、震颤,病理特征为纹状体黑质多巴胺能神经元的死亡,导致多巴胺分泌的减少,从而引起PD患者出现一系列的运动功能障碍。目前治疗帕金森病的药物只是以替代现象为主,并不能停止或缓解多巴胺能神经元减少。因此,对多巴胺能神经元的保护成为治疗帕金森病的主要环节,开发保护神经元的新药物将可以作为帕金森病治疗策略。
PD的发病机制,不仅受遗传因素决定,还受到环境因素影响。所以,家族遗传史、生活方式、食物摄入量等与帕金森病的发生有关。帕金森病的分子机制有自由基学说、神经元凋亡、内质网应激等。
吗啡于十九世纪初分离纯化得到,是一种具有强烈镇痛作用的化合物。吗啡对人体的作用与阿片受体有关。在动物和人体组织或体液中吗啡是来源于饮食,还存在有内源性吗啡,而人类的额叶皮质就会合成鸦片活性肽,人的其他细胞也产生并释放内源性吗啡生物碱。
最近,有研究表明,吗啡不仅具有镇痛作用,还具有保护神经元作用。吗啡是d-鸦片受体的激活剂,产生一系列应激反应。当高浓度的吗啡作用神经元时,可以诱导神经元凋亡。相反,低浓度的吗啡却可以保护神经元。目前,阿朴吗啡是临床上用于治疗帕金森病的一种常见药物。这证明吗啡和帕金森病有关。然而吗啡神经保护作用的分子机制还不是很明确。
1-甲基-4苯基吡啶离子(1-Methyl-4-phenylpyridinium ion, MPP+),是1-甲基-4-苯基-1,2,3,6-四氢吡啶(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP)的代谢产物,可以用来构建PD的细胞模型。有研究表明MPP+可以诱导细胞凋亡,并减少Trx/CyclinDl/Cdk5的表达。
我们使用MPP+处理PC12细胞构建帕金森病细胞模型来研究吗啡对细胞的保护机制。实验证明,低浓度的吗啡可以促进细胞增殖,吗啡也可以保护PC12细胞免受MPP+引起的细胞凋亡。吗啡诱导Trx/CyclinDl/Cdk5的表达,减少了MPP+导致神经元凋亡。吗啡的作用还可以激活Akt活性,抑制GSK38活性,从而保护细胞免于凋亡。Akt的抑制剂LY294002可以阻断吗啡的这种保护作用。这些结果表明,吗啡可以保护细胞免受MPP+引起的细胞凋亡,而这种保护作用是通过PI3K/Akt/GSK36信号通路实现的。
Parkinson's disease (PD) is a common neurodegenerative disease. Its clinical manifestations are muscle rigidity, tremor, and hypokinesia. The pathogenesis of PD is the apotosis of opaminergic neurons in striatum and substantia nigra, resulting in the decrease of dopamine secretion, which leds to a series of movement dysfunction. The current treatment on Parkinson's disease is replacement therapy, however, this could not stop or relieve the reduction of dopaminergic neurons. Therefore, the protection of dopaminergic neurons becomes the key treatment for Parkinson's disease. Development of new drugs to protect neurons will be a potential therapeutic strategy for Parkinson's disease.
The pathogenesis of PD is caused by genetic factors as well as by environmental factors. The development of PD is associated with family history, life style, food intaking, beverages, and so on. The molecular mechanisms on Parkinson's disease include free radical theory, neuronal apoptosis, endoplasmic reticulum stress and so on.
Morphine was isolated at the beginning of the 19th century, and is the strongest analgesic compounds. Its functions are related with opioid receptors. Morphine in animal and human tissue or fluids was believed to come from dietary origin. However, endogenous morphine also exsits, it is synthesized by frontal cortex, while other human cells produce and release the endogenous alkaloid morphine.
Recently, it has been showed that morphine has the analgesic effect, also has a role in protecting neurons. Morphine is the d-opiate receptor activator and induces a series of stress response. Treatment of high concentration of morphine induces neurons apoptosis. In contrast, low concentration of morphine can protect the neurons. At present, apomorphine is a clinic durg for the treatment of Parkinson's disease. This indicated that morphine is related to Parkinson's disease. However, the the molecular mechanism on morphine neuroprotective effect is not clear.
1-methyl-4-phenylpyridinium ion (MPP+), an active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), can be used to make the cell model of PD. Previous reports suggested that MPP+ can induce the apoptotic cell death and decrease the expression of Trx/CyclinD1/Cdk5.
We investigated mechanism on the cytoprotection of morphine by using PC12 cells treated by MPP+. Morphine proteced PC 12 cells from the apoptois induced by MPP+in PC12 cells. Morphine increased expression of Trx/CyclinDl/Cdk5, and also decreased the number of apoptotic cells. Morphine activates activity of Akt and inhibited GSK3βand ptotected cells from apoptosis. PI3K inhibitor, LY294002 blocked this cytoprotective effect of morphine. These results suggested that cytoprotective effect of morphine is through the PI3K/Akt/GSK3βpathway in the PC12 cells.
PD的发病机制,不仅受遗传因素决定,还受到环境因素影响。所以,家族遗传史、生活方式、食物摄入量等与帕金森病的发生有关。帕金森病的分子机制有自由基学说、神经元凋亡、内质网应激等。
吗啡于十九世纪初分离纯化得到,是一种具有强烈镇痛作用的化合物。吗啡对人体的作用与阿片受体有关。在动物和人体组织或体液中吗啡是来源于饮食,还存在有内源性吗啡,而人类的额叶皮质就会合成鸦片活性肽,人的其他细胞也产生并释放内源性吗啡生物碱。
最近,有研究表明,吗啡不仅具有镇痛作用,还具有保护神经元作用。吗啡是d-鸦片受体的激活剂,产生一系列应激反应。当高浓度的吗啡作用神经元时,可以诱导神经元凋亡。相反,低浓度的吗啡却可以保护神经元。目前,阿朴吗啡是临床上用于治疗帕金森病的一种常见药物。这证明吗啡和帕金森病有关。然而吗啡神经保护作用的分子机制还不是很明确。
1-甲基-4苯基吡啶离子(1-Methyl-4-phenylpyridinium ion, MPP+),是1-甲基-4-苯基-1,2,3,6-四氢吡啶(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP)的代谢产物,可以用来构建PD的细胞模型。有研究表明MPP+可以诱导细胞凋亡,并减少Trx/CyclinDl/Cdk5的表达。
我们使用MPP+处理PC12细胞构建帕金森病细胞模型来研究吗啡对细胞的保护机制。实验证明,低浓度的吗啡可以促进细胞增殖,吗啡也可以保护PC12细胞免受MPP+引起的细胞凋亡。吗啡诱导Trx/CyclinDl/Cdk5的表达,减少了MPP+导致神经元凋亡。吗啡的作用还可以激活Akt活性,抑制GSK38活性,从而保护细胞免于凋亡。Akt的抑制剂LY294002可以阻断吗啡的这种保护作用。这些结果表明,吗啡可以保护细胞免受MPP+引起的细胞凋亡,而这种保护作用是通过PI3K/Akt/GSK36信号通路实现的。
Parkinson's disease (PD) is a common neurodegenerative disease. Its clinical manifestations are muscle rigidity, tremor, and hypokinesia. The pathogenesis of PD is the apotosis of opaminergic neurons in striatum and substantia nigra, resulting in the decrease of dopamine secretion, which leds to a series of movement dysfunction. The current treatment on Parkinson's disease is replacement therapy, however, this could not stop or relieve the reduction of dopaminergic neurons. Therefore, the protection of dopaminergic neurons becomes the key treatment for Parkinson's disease. Development of new drugs to protect neurons will be a potential therapeutic strategy for Parkinson's disease.
The pathogenesis of PD is caused by genetic factors as well as by environmental factors. The development of PD is associated with family history, life style, food intaking, beverages, and so on. The molecular mechanisms on Parkinson's disease include free radical theory, neuronal apoptosis, endoplasmic reticulum stress and so on.
Morphine was isolated at the beginning of the 19th century, and is the strongest analgesic compounds. Its functions are related with opioid receptors. Morphine in animal and human tissue or fluids was believed to come from dietary origin. However, endogenous morphine also exsits, it is synthesized by frontal cortex, while other human cells produce and release the endogenous alkaloid morphine.
Recently, it has been showed that morphine has the analgesic effect, also has a role in protecting neurons. Morphine is the d-opiate receptor activator and induces a series of stress response. Treatment of high concentration of morphine induces neurons apoptosis. In contrast, low concentration of morphine can protect the neurons. At present, apomorphine is a clinic durg for the treatment of Parkinson's disease. This indicated that morphine is related to Parkinson's disease. However, the the molecular mechanism on morphine neuroprotective effect is not clear.
1-methyl-4-phenylpyridinium ion (MPP+), an active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), can be used to make the cell model of PD. Previous reports suggested that MPP+ can induce the apoptotic cell death and decrease the expression of Trx/CyclinD1/Cdk5.
We investigated mechanism on the cytoprotection of morphine by using PC12 cells treated by MPP+. Morphine proteced PC 12 cells from the apoptois induced by MPP+in PC12 cells. Morphine increased expression of Trx/CyclinDl/Cdk5, and also decreased the number of apoptotic cells. Morphine activates activity of Akt and inhibited GSK3βand ptotected cells from apoptosis. PI3K inhibitor, LY294002 blocked this cytoprotective effect of morphine. These results suggested that cytoprotective effect of morphine is through the PI3K/Akt/GSK3βpathway in the PC12 cells.
引文
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