白藜芦醇对酒精性周围神经损伤的保护作用
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摘要
临床研究和动物实验证明,饮酒不仅可以导致中枢神经系统的损伤,而且还会引起周围神经病变。长期以来,酒精对中枢神经系统影响作用的研究较为深入,而对酒精性周围神经病变的研究不够深入,其神经病理作用机制目前仍不清楚。最近研究结果表明,酒精导致的神经元死亡与氧化应激反应增加和氧化酶的诱导相关。
长期大量饮酒可导致酒精性周围神经病变(alcoholic peripheral neuropathy, APN)。APN是最常见的多发性周围神经病变之一。APN初期和主要症状为足部的疼痛,部分疼痛伴有烧灼感。部分患者亦可表现为手、小腿和足部的麻木或感觉缺失。APN的病理变化主要表现为轴突的病变,伴有节段性的脱髓鞘和髓鞘再生以及神经纤维的减少。虽然具体发病机制尚不清楚,但目前研究认为APN与氧化应激导致的自由基对神经的损伤、酒精对神经的直接毒性作用和长期饮酒导致的胶质细胞活化有关。
施万细胞(Schwann cells, SCs)是周围神经系统的髓鞘形成细胞,对周围神经的发育、功能和再生具有重要作用。SCs在多种炎症性、代谢性和遗传性多发神经病变中也有着重要作用。在许多生理和病理状态下,尤其是在神经损伤后,SCs可以通过表达脑源性神经营养因子(brain-derived neurotrophic factor, BDNF)、胶质细胞源性神经营养因子(glial cell line-derived neurotrophic factor, GDNF)、神经生长因子(nerve growth factor, NGF)等多种神经营养因子对轴突提供营养支持。SCs分泌的神经营养因子对于促进轴突生长、预防神经元凋亡具有重要作用。然而,在酒精处理的培养的SCs中,神经营养因子表达的变化尚不清楚。
白藜芦醇(resveratrol, Res)是存在于红酒、葡萄、蓝莓、花生等多种植物中的多醇化合物,可以调节多种细胞进程,并显示出多种保护和治疗功效。在Neuro2a细胞,Res能够激活腺苷酸活化蛋白激酶(AMP-activated protein kinase, AMPK)并促进轴突的生长。Res能够激活沉默信息调节器T1(silencing information regulator T1, SIRT1),可能对以轴突病变和神经退行性变为特征的疾病具有治疗作用。Res能够增强细胞的抗氧化反应能力,对某些病理改变所致的背根神经节(dorsal root ganglia, DRG)神经元氧化应激损伤具有修复作用。
为了进一步深入研究APN的病理发生机制,以及如何阻止APN的进程和研发APN的新的治疗手段,本课题利用体外培养的DRG神经元和SCs、以及APN大鼠动物模型,通过对多个分子生物学和生物化学指标的分析,以及动物的行为学观察,进一步探讨APN的病理发生机制及Res对APN的治疗作用。第一部分白藜芦醇对酒精损伤的背根神经节神经元的保护作用
在发育过程中,神经嵴区的细胞迁移形成DRG。全胚胎培养研究证明酒精可导致神经嵴区的细胞减少。酒精还可导致培养的孕14d胚胎DRG神经干细胞凋亡增加。抗氧化治疗对酒精诱导的神经损伤具有保护作用,这也表明氧化应激参与酒精导致的神经损伤。但是,尚不清楚抗氧化剂能否有效减少在发育过程中酒精诱导的神经元减少。由于酒精对DRG神经元的损伤目前尚无有效的治疗方法,抗氧化剂有可能减轻酒精导致的神经损伤。本课题利用体外培养的DRG神经元,研究体外环境中Res对酒精损伤的DRG神经元的保护作用。基于以上研究背景,本课题实验设计如下：
取第15d的胚胎大鼠DRG进行器官型培养和分散细胞培养。将酒精、Res、化合物C(Compound C,CC)以及尼克酰胺(nicotinamide,NCA)分别加入不同实验组DRG神经元培养基内。用微管相关蛋白2(microtubule-associatedprotein2,MAP2)标记神经元。计数由器官型培养的DRG组织块中生长出的神经纤维束和迁移出的神经元的数目。使用水溶性四唑盐-1(water soluble tetrazolium salt-1, WST-1)的方法检测DRG神经元的活性。使用Hoechst33342和末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记(terminal deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick-end-labeling, TUNEL)染色技术观察神经元的凋亡。使用荧光探针2',7'-二氯双氢荧光素二乙酸酯(2',7'-dichlorodihydrofluorescein diacetate, DCFH-DA)检测活性氧的含量。检测神经元中丙二醛(malondialdehyde, MDA),谷胱甘肽(glutathione, GSH),亚硝酸盐和过氧化物歧化酶(superoxide dismutase, SOD)的水平来分析氧化应激的程度。结果显示：
(1)Res可促进酒精损伤的器官型培养的DRG组织块神经纤维束的生长和单个神经元向周围的迁移。AMPK抑制剂CC和SIRT1抑制剂NCA可以抑制Res的作用。
(2)酒精孵育可降低分散培养的DRG神经元的活性,给予Res可提高酒精损伤的DRG神经元活性。AMPK抑制剂CC和SIRT1抑制剂NCA可以抑制Res的作用。
(3)酒精孵育可诱发分散培养的DRG神经元凋亡,Res可改善酒精诱发的DRG神经元凋亡。AMPK抑制剂CC和SIRT1抑制剂NCA可以阻断Res的抗凋亡作用。
(4)酒精孵育可增强分散培养的DRG神经元的氧化应激,应用Res可抑制酒精所致的氧化应激,降低MDA和亚硝酸盐的水平,增加GSH的含量和SOD的活性。
以上结果表明,Res对酒精损伤的器官型培养的DRG神经元的生长和再生具有促进作用；Res可增强酒精损伤的分散培养的DRG神经元的活性；Res可改善酒精损伤所致的DRG神经元凋亡和氧化应激；Res的神经保护作用与其对AMPK和SIRT1的激活有关,也与其抗氧化作用有关。因此,增强AMPK和SIRT1的活性有可能成为酒精对初级感觉神经元损伤的一种新的治疗方法,Res对DRG神经元的保护作用很可能使Res成为通过这一途径治疗酒精所致感觉神经元损伤的一个重要候选因子
第二部分白藜芦醇对酒精损伤的施万细胞的保护作用
SCs对DRG神经元正常形态和功能的维持具有重要的作用,酒精所致的DRG神经元损伤,很可能不但直接作用于神经元,也可能对SCs造成损伤从而间接影响DRG神经元功能的发挥。有研究显示,酒精可抑制培养的SCs增殖和髓鞘的形成,孕期和哺乳期长期大量饮酒可导致胶质细胞BDNF和NGF表达的改变,可能会损伤细胞内与细胞成活、生长、分化相关的信号通路,增加脑发育过程中细胞的死亡。然而,酒精对SCs的损伤程度及Res是否对酒精损伤的SCs具有保护作用目前仍不清楚。因此,本课题设计如下实验,研究Res对酒精损伤的SCs细胞的保护作用。
取新生大鼠双侧坐骨神经和臂丛神经进行SCs培养。培养的细胞分为6组：Res+酒精组；Res+CC+酒精组；Res+NCA+酒精组；Res+CC+NCA+酒精组；酒精组；对照组。用WST-1分析法检测Res对酒精引起的SCs细胞增殖和毒性的影响,用Hoechst33342和TUNEL染色技术观察SCs细胞的凋亡用实时荧光定量PCR技术检测BDNF.GDNF和NGF mRNA表达的变化,用Western blot技术检测BDNF.GDNF和NGF蛋白表达的变化。结果显示：
(1)酒精可降低SCs细胞的活性,Res可改善酒精损伤的SCs细胞的活性。AMPK抑制剂CC和SIRT1抑制剂NCA可以阻断Res的作用。
(2)酒精孵育可增加SCs细胞的凋亡,Res可抑制酒精引起的细胞凋亡。AMPK抑制剂CC和SIRT1抑制剂NCA可以阻断Res的抗凋亡作用。
(3)酒精孵育可促进SCs细胞NGF mRNA的表达,而对BDNF mRNA和GDNF mRNA的表达无显著影响作用；Res孵育可促进SCs细胞BDNF mRNA和GDNF mRNA的表达,而对NGF mRNA的表达无显著影响作用。
(4)酒精孵育可促进SCs细胞NGF、BDNF和GDNF蛋白的表达,而Res则可促进BDNF和GDNF的表达,对NGF的表达反而具有抑制作用。
以上结果表明,Res对酒精损伤的SCs细胞具有保护作用,Res很可能通过调节神经营养因子的表达而减少细胞的凋亡,从而发挥保护作用。Res对不同的神经营养因子的表达具有不同的调节作用,这表明Res对神经营养因子的表达的调节作用是复杂的。酒精孵育对SCs细胞不同神经营养因子表达产生不同的影响,这表明SCs细胞对所用酒精剂量的反应性,很可能是细胞的一种自我保护机制。酒精对SCs细胞的毒性作用机制及Res对SCs细胞的保护作用及其机制尚有待于进一步探讨。
第三部分白藜芦醇对大鼠酒精性周围神经病变的保护作用
氧化应激是导致周围神经病变出现神经痛的重要因素之一。细胞因子可直接与伤害感受器作用并引起炎症反应,导致痛觉过敏。Res可通过清除ROS并作用于氧化还原调节蛋白产生神经保护作用。促炎症细胞因子可介导神经元凋亡和周围神经病理性疼痛,长期饮用大量酒精所致的神经病理性疼痛是否与促炎症细胞因子的产生有关以及Res对APN的治疗作用尚需要进一步探讨。
本课题利用酒精诱发的APN疼痛的动物模型,通过检测大鼠的痛觉行为学改变,观察坐骨神经光镜水平的形态学和电镜水平的超微结构改变,以及检测坐骨神经内MDA、GSH、亚硝酸盐、SOD、肿瘤坏死因子-α(tumor nectosis factor-α, TNF-α)和白细胞介素-6(interleukin-6, IL-6)水平的变化,综合分析酒精所致APN的病理发生机制及Res对酒精诱发的APN的治疗作用。结果显示：
(1)大鼠经酒精灌胃6w后即可出现触觉异常性疼痛和热痛觉过敏,至第12w,触觉异常性疼痛和热痛觉过敏更加明显。
(2)对于酒精诱发的APN疼痛大鼠,应用Res后可缓解酒精所致的触觉异常性疼痛和热痛觉过敏。
(3)给APN大鼠应用Res后,坐骨神经光镜水平的形态学和电镜水平的超微结构均出现明显改善。
(4)酒精诱发的APN大鼠,坐骨神经组织的氧化应激反应增强,应用Res可抑制酒精诱发的氧化应激反应。
(5)酒精可引起坐骨神经组织内促炎症细胞因子的水平升高,应用Res可抑制这些促炎症细胞因子水平的上升。
以上结果表明,给大鼠长期饮用酒精可对周围神经组织产生明显的损伤作用,并导致动物的痛觉行为学发生改变。酒精对周围神经组织的损伤作用是多方面的,不仅直接引起神经超微结构的改变,而且还增强氧化应激反应和促进促炎症细胞因子的表达,这些变化可能会进一步加重神经的形态学变化。应用Res可从多个方面或层次改善酒精所致的周围神经损伤。这些研究结果不仅对酒精所致的周围神经损伤研究提供了新的实验资料,而且对开发APN的新的治疗措施提供了具有指导意义的理论基础和实验依据。不可否认,本课题的研究结果对于将来采用Res和其衍生物预防或治疗APN具有实际指导意义。
Clinical studies and research in animals have established that ethanol (EtOH) consumption results in damage not only to the central nervous systems but also to the peripheral nervous systems. The effects of EtOH on the central nervous system have been well developed for a long time, while the research on the effects of EtOH on alcoholic peripheral neuropathy is not enough and the pathological mechanism is still unclear. Recently, many studies have demonstrated that EtOH-induced neuronal death is related to increases in oxidative stress that coincide with the induction of oxidative enzymes.
Excessive drinking, usually over years, can lead to alcoholic peripheral neuropathy (APN). In the condition of high alcohol intake,36.8%drinkers fulfilled criteria of peripheral neuropathy. The APN is one of the most common polyneuropathies all over the world. The initial and major symptom of APN is pain with or without burning sensations in the feet, and there may be numbness or tingling in the hands, legs and feet. The pathologic change is an axonal neuropathy characterized by segmental de/remyelination and a reduction in nerve fibers. Although the exact mechanisms is remain unknown, several pathophysiological processes take responsibility for APN, including oxidative stress leading to free radical damage to nerves, direct toxic effect of alcohol and activation of spinal cord microglia after chronic alcohol consumption.
Schwann cells (SCs) are the myelin forming cells in the peripheral nervous system and contribute to the development, function and regeneration of peripheral nerves. They play a key role in the pathology of various inflammatory, metabolic and hereditary polyneuropathies. SCs provide trophic support to axons via expression of various neurotrophic factors, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), especially after nerve injury. Ethanol (EtOH) adversely affected both SCs proliferation and myelin formation in culture. The secretion of neurotrophic factors by SCs is necessary to promote axon growth and prevent neurons from initiating apoptosis. However, the alterations of neurotrophic factors in EtOH treated SCs are still unknown.
Resveratrol (Res), a polyphenolic compound found in grapes, red wine, berries, peanuts and other plants, has been shown to regulate many cellular processes and to display multiple protective and therapeutic effects. Res has been shown to activate AMP-activated protein kinase (AMPK) and promote robust neurite outgrowth in Neuro2a cells. Res also may be effective for the treatment of diseases characterized by axonopathy and neurodegeneration due to its ability to activate sirtuin1(SIRT1). Res has been shown to activate the antioxidant response and prevent hyperglycemic oxidative stress in dorsal root ganglia (DRG) neurons.
In order to study the pathogenesis of APN, prevent the progression of APN and find new therapeutic strategy, in this study, using the cultured DRG neurons, SCs and the animal model of APN, we estimated the therapeutic effect of Res on APN and discussed the pathological mechanism of APN by analyzing the molecular biology/biochemistry index and observing the animal behaviors.
Part I Neuroprotective effects of resveratrol on dorsal root ganglion neurons with neurotoxicity induced by ethanol
EtOH treatment caused the loss of cells in the neural crest region, which migration leading to DRG formation, in whole embryo culture study and leading to increased apoptosis in embryonic day14(E14) DRG neural stem cells. The beneficial effects of antioxidant therapy during EtOH exposure also support the role of oxidative stress in EtOH-induced neurotoxicity. However, whether antioxidants are effective in attenuating the EtOH-induced loss of neurons during development is still unknown. While EtOH-induced injury to DRG neurons is marginally relieved by the available therapies, antioxidants seem to be effective for alleviating EtOH-induced nerve injury. In this study, we investigated the neuroprotective efficacy of Res in EtOH treated DRG neurons in vitro. We hypothesized that Res administration in embryonic DRG culture model would improve neuronal survival by suppressing oxidative stress. The present study focused on the effects of Res on neurite outgrowth, neuronal migration, apoptosis and oxidative stress of embryonic DRG neurons with EtOH-induced toxicity in vitro. The experiments were designed as follows:
The embryonic day15rats were used for dissociated and organotypic DRG culture preparations. EtOH, Res, Compound C (CC) or nicotinamide (NCA) was applied as a single bolus directly to the culture media. Microtubule-associated protein2(MAP2) fluorescent label and observe the cultured cells. The number of nerve fiber bundles extending and the neurons migrating from the DRG explants was counted. The viability of the DRG neurons was detected using a water soluble tetrazolium salt-1(WST-1) method. Hoechst33342and terminal deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick-end-labeling (TUNEL) staining was used to observe apoptotic neuronal cell death. The production of intracellular ROS was measured with2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA). The malondialdehyde (MDA), glutathione (GSH), nitrite level and superoxide dismutase (SOD) activity were measured to assay the oxidative stress. The results are as follows:
(1) Res significantly promoted the outgrowth of neuron fibers and the migration of neurons compared to that of the EtOH group, whereas the AMPK inhibitor CC and the SIRT1inhibitor NCA inhibited the promoting effect of Res.
(2) EtOH decreased cell viability, the administration of Res improved cell viability significantly. This effect of Res was inhibited by the AMPK inhibitor CC and the SIRT1inhibitor NCA.
(3) EtOH exposure increased the number of apoptotic neurons compared with the control group. Res reduced the percentage of apoptotic cells compared to the cells treated with EtOH alone. Treatment with AMPK inhibitor CC and the SIRT1reversed the protective effect of Res.
(4) Res inhibited the oxi dative stress that induced by EtOH, decreased the levels of MDA and nitrite, and increased the level of GSH and SOD activity.
The data in this study indicate that:Res promoted the outgrowth of neuron fibers and the migration of neurons from the organotypic culture of DRG; Res inhibited the death and apoptosis of DRG neurons that induced by EtOH. These neuroprotective effects are associated with the activation of AMPK and SIRT1by Res as well as its antioxidative effect. These findings suggest that novel therapeutic strategies designed to increase the activation of AMPK and SIRT1may be effective for reducing EtOH induced neurotoxicity of embryonic primary sensory neurons. Res and its derivative may be good candidates for the prevention and/or treatment of these diseases.
Part II The protective effects of resveratrol on Schwann cells with toxicity induced by ethanol in vitro
SCs contribute to the maintenance of peripheral nerve morphology and function. Besides the direct neurotoxicity of EtOH, EtOH may also induce cell injury to SCs and influence the function of DRG neurons indirectly. EtOH adversely affected both SCs proliferation and myelin formation in culture. Chronic EtOH intake during gestation and lactation induced alterations in the expression of BDNF and NGF levels might impair intracellular signaling pathways involved in cell survival, growth and differentiation, leading to enhanced natural cell death during brain development. Several researches have demonstrated that Res is capable to regulate the expression of neurotrophic factors. In the present study, we hypothesized that Res administration would improve cell survival and affect expression of neurotrophic factors (BDNF, GDNF, and NGFF) of SCs with EtOH treatment in vitro. The experiments were designed as follows:
The bilateral sciatic nerves and brachial plexus were removed from neonatal rats to isolation and culture SCs. The cultured cells were divided into6groups:EtOH+Res; EtOH+Res+CC;:EtOH+Res+NCA; EtOH+Res+CC+NCA; EtOH; control. Using the WST-1to assay the effects of Res on cell proliferation and cytotoxicity that induced by EtOH. Hoechst33342and TUNEL staining was used to observe apoptotic SCs death. The expression of BDNF, GDNF, and NGF mRNAs were analyzed by real time-PCR. The protein levels of BDNF, GDNF, and NGF were detected by western blotting. The results are as follows:
(1) Compared to the control group, treatment with EtOH possessed decreased cell viability. Administration of Res improved cell viability significantly. The effect of Res was inhibited by AMPK inhibitor CC and SIRT1inhibitor NCA.
(2) EtOH exposure increased the number of apoptotic cells compared with the control group. Res reduced the percentage of apoptotic cells, treatment with CC and NCA reversed the protective effect of Res on the EtOH-induced apoptosis in SCs.
(3) NGF mRNA expression significantly increased in EtOH-treated SCs. The expression of BDNF and GDNF mRNA increased significantly after Res administration as compared to that of the control group.
(4) BDNF, GDNF, and NGF protein levels increased significantly in EtOH treated SCs. Administration of Res increased the protein levels of BDNF and GDNF significantly but inhibited the increase of NGF protein levels.
The data in the present study indicate that Res protects SCs from EtOH-induced cell death and alters the expression of neurotrophic factors in EtOH-treated SCs. The regulating effects of Res on three neurotrophic factors are different, which indicates that the effects of Res on neurotrophic factors expression are complicated.
The effects of Res on cell survival and the regulation of neurotrophic factors expression in EtOH-treated SCs suggest that Res and its derivative may play a beneficial role in ameliorating the EtOH-induced pathologic changes in the peripheral and/or central nervous system. As the protective effect is associated with the activation of AMPK-SIRT1pathway, novel therapeutic strategies designed to increase the activation of AMPK and SIRT1may be effective for the treatment of diseases characterized by myelin and axon lesion that induced by EtOH. The different expression of the neurotrophic factors after EtOH incubation suggests that the reaction of SCs is likely to be a protective action of cells. The mechanisms of the toxic effects of EtOH and the protective effects of Res on SCs remain to be further studied.
Part Ⅲ Resveratrol relieves alcoholic peripheral neuropathy in rats
Oxidative stress is one of the most significant factors in the development and maintenance of neuropathic pain in peripheral neuropathy. Cytokines show a direct activation of nociceptors and potentiate the inflammatory response which causes pain hypersensitivity. Studies indicate that Res exhibits neuroprotective effects by scavenging ROS and acting at redox regulating proteins. The pro inflammatory cytokines mediates neuron apoptosis and neuropathic pain of peripheral nervous system. A proper understanding of the effects of proinflammatory cytokines and Res on experimental chronic APN rat is highly important for providing a clue and strengthening the rationale of Res as effective therapeutic drug in human APN.
In this study, the alcoholic peripheral neuropathic pain animal model was induced by intragastric administration of EtOH. The mechanical hyperalgesia was tested by von Frey filaments. The thermal hyperalgesia was tested by a radiant heat generator. The micro structure of the sciatic nerve was observed. The MDA, GSH, nitrite level and SOD activity were measured to assay the oxidative stress. The tumor necrosis factor-a (TNF-a) and interleukin-6(IL-6) level were measured to assay the inflammatory status.
The results are as follows:
(1) The mechanical and thermal hyperalgesia appeared at the6th w after administration of EtOH and lasted to the12th w.
(2) Treatment with Res significantly reversed the mechanical and thermal hyperalgesia which induced by EtOH.
(3) Res treatment could partially reverse the morphological alterations of sciatic nerve in APN rats.
(4) Res inhibited the oxidative stress that induced by EtOH in the sciatic nerve.
(5) Res inhibited the levels of inflammatory cytokines that induced by EtOH in the sciatic nerve.
The present study demonstrated that, chronic EtOH administration induced peripheral nerve injury and behavior changes in rats. EtOH not only induced the morphological changes of the sciatic nerve but also enhanced the oxidative stress and the expression of pro inflammatory factors. Res may play an important role in relief of pathologic changes and neuropathic pain in APN through inhibiting the oxidative stress and inflammatory cytokine levels in the sciatic nerve. These findings provide rationale and experimental evidence for the development of Res therapeutic strategy to alleviate APN.
长期大量饮酒可导致酒精性周围神经病变(alcoholic peripheral neuropathy, APN)。APN是最常见的多发性周围神经病变之一。APN初期和主要症状为足部的疼痛,部分疼痛伴有烧灼感。部分患者亦可表现为手、小腿和足部的麻木或感觉缺失。APN的病理变化主要表现为轴突的病变,伴有节段性的脱髓鞘和髓鞘再生以及神经纤维的减少。虽然具体发病机制尚不清楚,但目前研究认为APN与氧化应激导致的自由基对神经的损伤、酒精对神经的直接毒性作用和长期饮酒导致的胶质细胞活化有关。
施万细胞(Schwann cells, SCs)是周围神经系统的髓鞘形成细胞,对周围神经的发育、功能和再生具有重要作用。SCs在多种炎症性、代谢性和遗传性多发神经病变中也有着重要作用。在许多生理和病理状态下,尤其是在神经损伤后,SCs可以通过表达脑源性神经营养因子(brain-derived neurotrophic factor, BDNF)、胶质细胞源性神经营养因子(glial cell line-derived neurotrophic factor, GDNF)、神经生长因子(nerve growth factor, NGF)等多种神经营养因子对轴突提供营养支持。SCs分泌的神经营养因子对于促进轴突生长、预防神经元凋亡具有重要作用。然而,在酒精处理的培养的SCs中,神经营养因子表达的变化尚不清楚。
白藜芦醇(resveratrol, Res)是存在于红酒、葡萄、蓝莓、花生等多种植物中的多醇化合物,可以调节多种细胞进程,并显示出多种保护和治疗功效。在Neuro2a细胞,Res能够激活腺苷酸活化蛋白激酶(AMP-activated protein kinase, AMPK)并促进轴突的生长。Res能够激活沉默信息调节器T1(silencing information regulator T1, SIRT1),可能对以轴突病变和神经退行性变为特征的疾病具有治疗作用。Res能够增强细胞的抗氧化反应能力,对某些病理改变所致的背根神经节(dorsal root ganglia, DRG)神经元氧化应激损伤具有修复作用。
为了进一步深入研究APN的病理发生机制,以及如何阻止APN的进程和研发APN的新的治疗手段,本课题利用体外培养的DRG神经元和SCs、以及APN大鼠动物模型,通过对多个分子生物学和生物化学指标的分析,以及动物的行为学观察,进一步探讨APN的病理发生机制及Res对APN的治疗作用。第一部分白藜芦醇对酒精损伤的背根神经节神经元的保护作用
在发育过程中,神经嵴区的细胞迁移形成DRG。全胚胎培养研究证明酒精可导致神经嵴区的细胞减少。酒精还可导致培养的孕14d胚胎DRG神经干细胞凋亡增加。抗氧化治疗对酒精诱导的神经损伤具有保护作用,这也表明氧化应激参与酒精导致的神经损伤。但是,尚不清楚抗氧化剂能否有效减少在发育过程中酒精诱导的神经元减少。由于酒精对DRG神经元的损伤目前尚无有效的治疗方法,抗氧化剂有可能减轻酒精导致的神经损伤。本课题利用体外培养的DRG神经元,研究体外环境中Res对酒精损伤的DRG神经元的保护作用。基于以上研究背景,本课题实验设计如下：
取第15d的胚胎大鼠DRG进行器官型培养和分散细胞培养。将酒精、Res、化合物C(Compound C,CC)以及尼克酰胺(nicotinamide,NCA)分别加入不同实验组DRG神经元培养基内。用微管相关蛋白2(microtubule-associatedprotein2,MAP2)标记神经元。计数由器官型培养的DRG组织块中生长出的神经纤维束和迁移出的神经元的数目。使用水溶性四唑盐-1(water soluble tetrazolium salt-1, WST-1)的方法检测DRG神经元的活性。使用Hoechst33342和末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记(terminal deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick-end-labeling, TUNEL)染色技术观察神经元的凋亡。使用荧光探针2',7'-二氯双氢荧光素二乙酸酯(2',7'-dichlorodihydrofluorescein diacetate, DCFH-DA)检测活性氧的含量。检测神经元中丙二醛(malondialdehyde, MDA),谷胱甘肽(glutathione, GSH),亚硝酸盐和过氧化物歧化酶(superoxide dismutase, SOD)的水平来分析氧化应激的程度。结果显示：
(1)Res可促进酒精损伤的器官型培养的DRG组织块神经纤维束的生长和单个神经元向周围的迁移。AMPK抑制剂CC和SIRT1抑制剂NCA可以抑制Res的作用。
(2)酒精孵育可降低分散培养的DRG神经元的活性,给予Res可提高酒精损伤的DRG神经元活性。AMPK抑制剂CC和SIRT1抑制剂NCA可以抑制Res的作用。
(3)酒精孵育可诱发分散培养的DRG神经元凋亡,Res可改善酒精诱发的DRG神经元凋亡。AMPK抑制剂CC和SIRT1抑制剂NCA可以阻断Res的抗凋亡作用。
(4)酒精孵育可增强分散培养的DRG神经元的氧化应激,应用Res可抑制酒精所致的氧化应激,降低MDA和亚硝酸盐的水平,增加GSH的含量和SOD的活性。
以上结果表明,Res对酒精损伤的器官型培养的DRG神经元的生长和再生具有促进作用；Res可增强酒精损伤的分散培养的DRG神经元的活性；Res可改善酒精损伤所致的DRG神经元凋亡和氧化应激；Res的神经保护作用与其对AMPK和SIRT1的激活有关,也与其抗氧化作用有关。因此,增强AMPK和SIRT1的活性有可能成为酒精对初级感觉神经元损伤的一种新的治疗方法,Res对DRG神经元的保护作用很可能使Res成为通过这一途径治疗酒精所致感觉神经元损伤的一个重要候选因子
第二部分白藜芦醇对酒精损伤的施万细胞的保护作用
SCs对DRG神经元正常形态和功能的维持具有重要的作用,酒精所致的DRG神经元损伤,很可能不但直接作用于神经元,也可能对SCs造成损伤从而间接影响DRG神经元功能的发挥。有研究显示,酒精可抑制培养的SCs增殖和髓鞘的形成,孕期和哺乳期长期大量饮酒可导致胶质细胞BDNF和NGF表达的改变,可能会损伤细胞内与细胞成活、生长、分化相关的信号通路,增加脑发育过程中细胞的死亡。然而,酒精对SCs的损伤程度及Res是否对酒精损伤的SCs具有保护作用目前仍不清楚。因此,本课题设计如下实验,研究Res对酒精损伤的SCs细胞的保护作用。
取新生大鼠双侧坐骨神经和臂丛神经进行SCs培养。培养的细胞分为6组：Res+酒精组；Res+CC+酒精组；Res+NCA+酒精组；Res+CC+NCA+酒精组；酒精组；对照组。用WST-1分析法检测Res对酒精引起的SCs细胞增殖和毒性的影响,用Hoechst33342和TUNEL染色技术观察SCs细胞的凋亡用实时荧光定量PCR技术检测BDNF.GDNF和NGF mRNA表达的变化,用Western blot技术检测BDNF.GDNF和NGF蛋白表达的变化。结果显示：
(1)酒精可降低SCs细胞的活性,Res可改善酒精损伤的SCs细胞的活性。AMPK抑制剂CC和SIRT1抑制剂NCA可以阻断Res的作用。
(2)酒精孵育可增加SCs细胞的凋亡,Res可抑制酒精引起的细胞凋亡。AMPK抑制剂CC和SIRT1抑制剂NCA可以阻断Res的抗凋亡作用。
(3)酒精孵育可促进SCs细胞NGF mRNA的表达,而对BDNF mRNA和GDNF mRNA的表达无显著影响作用；Res孵育可促进SCs细胞BDNF mRNA和GDNF mRNA的表达,而对NGF mRNA的表达无显著影响作用。
(4)酒精孵育可促进SCs细胞NGF、BDNF和GDNF蛋白的表达,而Res则可促进BDNF和GDNF的表达,对NGF的表达反而具有抑制作用。
以上结果表明,Res对酒精损伤的SCs细胞具有保护作用,Res很可能通过调节神经营养因子的表达而减少细胞的凋亡,从而发挥保护作用。Res对不同的神经营养因子的表达具有不同的调节作用,这表明Res对神经营养因子的表达的调节作用是复杂的。酒精孵育对SCs细胞不同神经营养因子表达产生不同的影响,这表明SCs细胞对所用酒精剂量的反应性,很可能是细胞的一种自我保护机制。酒精对SCs细胞的毒性作用机制及Res对SCs细胞的保护作用及其机制尚有待于进一步探讨。
第三部分白藜芦醇对大鼠酒精性周围神经病变的保护作用
氧化应激是导致周围神经病变出现神经痛的重要因素之一。细胞因子可直接与伤害感受器作用并引起炎症反应,导致痛觉过敏。Res可通过清除ROS并作用于氧化还原调节蛋白产生神经保护作用。促炎症细胞因子可介导神经元凋亡和周围神经病理性疼痛,长期饮用大量酒精所致的神经病理性疼痛是否与促炎症细胞因子的产生有关以及Res对APN的治疗作用尚需要进一步探讨。
本课题利用酒精诱发的APN疼痛的动物模型,通过检测大鼠的痛觉行为学改变,观察坐骨神经光镜水平的形态学和电镜水平的超微结构改变,以及检测坐骨神经内MDA、GSH、亚硝酸盐、SOD、肿瘤坏死因子-α(tumor nectosis factor-α, TNF-α)和白细胞介素-6(interleukin-6, IL-6)水平的变化,综合分析酒精所致APN的病理发生机制及Res对酒精诱发的APN的治疗作用。结果显示：
(1)大鼠经酒精灌胃6w后即可出现触觉异常性疼痛和热痛觉过敏,至第12w,触觉异常性疼痛和热痛觉过敏更加明显。
(2)对于酒精诱发的APN疼痛大鼠,应用Res后可缓解酒精所致的触觉异常性疼痛和热痛觉过敏。
(3)给APN大鼠应用Res后,坐骨神经光镜水平的形态学和电镜水平的超微结构均出现明显改善。
(4)酒精诱发的APN大鼠,坐骨神经组织的氧化应激反应增强,应用Res可抑制酒精诱发的氧化应激反应。
(5)酒精可引起坐骨神经组织内促炎症细胞因子的水平升高,应用Res可抑制这些促炎症细胞因子水平的上升。
以上结果表明,给大鼠长期饮用酒精可对周围神经组织产生明显的损伤作用,并导致动物的痛觉行为学发生改变。酒精对周围神经组织的损伤作用是多方面的,不仅直接引起神经超微结构的改变,而且还增强氧化应激反应和促进促炎症细胞因子的表达,这些变化可能会进一步加重神经的形态学变化。应用Res可从多个方面或层次改善酒精所致的周围神经损伤。这些研究结果不仅对酒精所致的周围神经损伤研究提供了新的实验资料,而且对开发APN的新的治疗措施提供了具有指导意义的理论基础和实验依据。不可否认,本课题的研究结果对于将来采用Res和其衍生物预防或治疗APN具有实际指导意义。
Clinical studies and research in animals have established that ethanol (EtOH) consumption results in damage not only to the central nervous systems but also to the peripheral nervous systems. The effects of EtOH on the central nervous system have been well developed for a long time, while the research on the effects of EtOH on alcoholic peripheral neuropathy is not enough and the pathological mechanism is still unclear. Recently, many studies have demonstrated that EtOH-induced neuronal death is related to increases in oxidative stress that coincide with the induction of oxidative enzymes.
Excessive drinking, usually over years, can lead to alcoholic peripheral neuropathy (APN). In the condition of high alcohol intake,36.8%drinkers fulfilled criteria of peripheral neuropathy. The APN is one of the most common polyneuropathies all over the world. The initial and major symptom of APN is pain with or without burning sensations in the feet, and there may be numbness or tingling in the hands, legs and feet. The pathologic change is an axonal neuropathy characterized by segmental de/remyelination and a reduction in nerve fibers. Although the exact mechanisms is remain unknown, several pathophysiological processes take responsibility for APN, including oxidative stress leading to free radical damage to nerves, direct toxic effect of alcohol and activation of spinal cord microglia after chronic alcohol consumption.
Schwann cells (SCs) are the myelin forming cells in the peripheral nervous system and contribute to the development, function and regeneration of peripheral nerves. They play a key role in the pathology of various inflammatory, metabolic and hereditary polyneuropathies. SCs provide trophic support to axons via expression of various neurotrophic factors, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), especially after nerve injury. Ethanol (EtOH) adversely affected both SCs proliferation and myelin formation in culture. The secretion of neurotrophic factors by SCs is necessary to promote axon growth and prevent neurons from initiating apoptosis. However, the alterations of neurotrophic factors in EtOH treated SCs are still unknown.
Resveratrol (Res), a polyphenolic compound found in grapes, red wine, berries, peanuts and other plants, has been shown to regulate many cellular processes and to display multiple protective and therapeutic effects. Res has been shown to activate AMP-activated protein kinase (AMPK) and promote robust neurite outgrowth in Neuro2a cells. Res also may be effective for the treatment of diseases characterized by axonopathy and neurodegeneration due to its ability to activate sirtuin1(SIRT1). Res has been shown to activate the antioxidant response and prevent hyperglycemic oxidative stress in dorsal root ganglia (DRG) neurons.
In order to study the pathogenesis of APN, prevent the progression of APN and find new therapeutic strategy, in this study, using the cultured DRG neurons, SCs and the animal model of APN, we estimated the therapeutic effect of Res on APN and discussed the pathological mechanism of APN by analyzing the molecular biology/biochemistry index and observing the animal behaviors.
Part I Neuroprotective effects of resveratrol on dorsal root ganglion neurons with neurotoxicity induced by ethanol
EtOH treatment caused the loss of cells in the neural crest region, which migration leading to DRG formation, in whole embryo culture study and leading to increased apoptosis in embryonic day14(E14) DRG neural stem cells. The beneficial effects of antioxidant therapy during EtOH exposure also support the role of oxidative stress in EtOH-induced neurotoxicity. However, whether antioxidants are effective in attenuating the EtOH-induced loss of neurons during development is still unknown. While EtOH-induced injury to DRG neurons is marginally relieved by the available therapies, antioxidants seem to be effective for alleviating EtOH-induced nerve injury. In this study, we investigated the neuroprotective efficacy of Res in EtOH treated DRG neurons in vitro. We hypothesized that Res administration in embryonic DRG culture model would improve neuronal survival by suppressing oxidative stress. The present study focused on the effects of Res on neurite outgrowth, neuronal migration, apoptosis and oxidative stress of embryonic DRG neurons with EtOH-induced toxicity in vitro. The experiments were designed as follows:
The embryonic day15rats were used for dissociated and organotypic DRG culture preparations. EtOH, Res, Compound C (CC) or nicotinamide (NCA) was applied as a single bolus directly to the culture media. Microtubule-associated protein2(MAP2) fluorescent label and observe the cultured cells. The number of nerve fiber bundles extending and the neurons migrating from the DRG explants was counted. The viability of the DRG neurons was detected using a water soluble tetrazolium salt-1(WST-1) method. Hoechst33342and terminal deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick-end-labeling (TUNEL) staining was used to observe apoptotic neuronal cell death. The production of intracellular ROS was measured with2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA). The malondialdehyde (MDA), glutathione (GSH), nitrite level and superoxide dismutase (SOD) activity were measured to assay the oxidative stress. The results are as follows:
(1) Res significantly promoted the outgrowth of neuron fibers and the migration of neurons compared to that of the EtOH group, whereas the AMPK inhibitor CC and the SIRT1inhibitor NCA inhibited the promoting effect of Res.
(2) EtOH decreased cell viability, the administration of Res improved cell viability significantly. This effect of Res was inhibited by the AMPK inhibitor CC and the SIRT1inhibitor NCA.
(3) EtOH exposure increased the number of apoptotic neurons compared with the control group. Res reduced the percentage of apoptotic cells compared to the cells treated with EtOH alone. Treatment with AMPK inhibitor CC and the SIRT1reversed the protective effect of Res.
(4) Res inhibited the oxi dative stress that induced by EtOH, decreased the levels of MDA and nitrite, and increased the level of GSH and SOD activity.
The data in this study indicate that:Res promoted the outgrowth of neuron fibers and the migration of neurons from the organotypic culture of DRG; Res inhibited the death and apoptosis of DRG neurons that induced by EtOH. These neuroprotective effects are associated with the activation of AMPK and SIRT1by Res as well as its antioxidative effect. These findings suggest that novel therapeutic strategies designed to increase the activation of AMPK and SIRT1may be effective for reducing EtOH induced neurotoxicity of embryonic primary sensory neurons. Res and its derivative may be good candidates for the prevention and/or treatment of these diseases.
Part II The protective effects of resveratrol on Schwann cells with toxicity induced by ethanol in vitro
SCs contribute to the maintenance of peripheral nerve morphology and function. Besides the direct neurotoxicity of EtOH, EtOH may also induce cell injury to SCs and influence the function of DRG neurons indirectly. EtOH adversely affected both SCs proliferation and myelin formation in culture. Chronic EtOH intake during gestation and lactation induced alterations in the expression of BDNF and NGF levels might impair intracellular signaling pathways involved in cell survival, growth and differentiation, leading to enhanced natural cell death during brain development. Several researches have demonstrated that Res is capable to regulate the expression of neurotrophic factors. In the present study, we hypothesized that Res administration would improve cell survival and affect expression of neurotrophic factors (BDNF, GDNF, and NGFF) of SCs with EtOH treatment in vitro. The experiments were designed as follows:
The bilateral sciatic nerves and brachial plexus were removed from neonatal rats to isolation and culture SCs. The cultured cells were divided into6groups:EtOH+Res; EtOH+Res+CC;:EtOH+Res+NCA; EtOH+Res+CC+NCA; EtOH; control. Using the WST-1to assay the effects of Res on cell proliferation and cytotoxicity that induced by EtOH. Hoechst33342and TUNEL staining was used to observe apoptotic SCs death. The expression of BDNF, GDNF, and NGF mRNAs were analyzed by real time-PCR. The protein levels of BDNF, GDNF, and NGF were detected by western blotting. The results are as follows:
(1) Compared to the control group, treatment with EtOH possessed decreased cell viability. Administration of Res improved cell viability significantly. The effect of Res was inhibited by AMPK inhibitor CC and SIRT1inhibitor NCA.
(2) EtOH exposure increased the number of apoptotic cells compared with the control group. Res reduced the percentage of apoptotic cells, treatment with CC and NCA reversed the protective effect of Res on the EtOH-induced apoptosis in SCs.
(3) NGF mRNA expression significantly increased in EtOH-treated SCs. The expression of BDNF and GDNF mRNA increased significantly after Res administration as compared to that of the control group.
(4) BDNF, GDNF, and NGF protein levels increased significantly in EtOH treated SCs. Administration of Res increased the protein levels of BDNF and GDNF significantly but inhibited the increase of NGF protein levels.
The data in the present study indicate that Res protects SCs from EtOH-induced cell death and alters the expression of neurotrophic factors in EtOH-treated SCs. The regulating effects of Res on three neurotrophic factors are different, which indicates that the effects of Res on neurotrophic factors expression are complicated.
The effects of Res on cell survival and the regulation of neurotrophic factors expression in EtOH-treated SCs suggest that Res and its derivative may play a beneficial role in ameliorating the EtOH-induced pathologic changes in the peripheral and/or central nervous system. As the protective effect is associated with the activation of AMPK-SIRT1pathway, novel therapeutic strategies designed to increase the activation of AMPK and SIRT1may be effective for the treatment of diseases characterized by myelin and axon lesion that induced by EtOH. The different expression of the neurotrophic factors after EtOH incubation suggests that the reaction of SCs is likely to be a protective action of cells. The mechanisms of the toxic effects of EtOH and the protective effects of Res on SCs remain to be further studied.
Part Ⅲ Resveratrol relieves alcoholic peripheral neuropathy in rats
Oxidative stress is one of the most significant factors in the development and maintenance of neuropathic pain in peripheral neuropathy. Cytokines show a direct activation of nociceptors and potentiate the inflammatory response which causes pain hypersensitivity. Studies indicate that Res exhibits neuroprotective effects by scavenging ROS and acting at redox regulating proteins. The pro inflammatory cytokines mediates neuron apoptosis and neuropathic pain of peripheral nervous system. A proper understanding of the effects of proinflammatory cytokines and Res on experimental chronic APN rat is highly important for providing a clue and strengthening the rationale of Res as effective therapeutic drug in human APN.
In this study, the alcoholic peripheral neuropathic pain animal model was induced by intragastric administration of EtOH. The mechanical hyperalgesia was tested by von Frey filaments. The thermal hyperalgesia was tested by a radiant heat generator. The micro structure of the sciatic nerve was observed. The MDA, GSH, nitrite level and SOD activity were measured to assay the oxidative stress. The tumor necrosis factor-a (TNF-a) and interleukin-6(IL-6) level were measured to assay the inflammatory status.
The results are as follows:
(1) The mechanical and thermal hyperalgesia appeared at the6th w after administration of EtOH and lasted to the12th w.
(2) Treatment with Res significantly reversed the mechanical and thermal hyperalgesia which induced by EtOH.
(3) Res treatment could partially reverse the morphological alterations of sciatic nerve in APN rats.
(4) Res inhibited the oxidative stress that induced by EtOH in the sciatic nerve.
(5) Res inhibited the levels of inflammatory cytokines that induced by EtOH in the sciatic nerve.
The present study demonstrated that, chronic EtOH administration induced peripheral nerve injury and behavior changes in rats. EtOH not only induced the morphological changes of the sciatic nerve but also enhanced the oxidative stress and the expression of pro inflammatory factors. Res may play an important role in relief of pathologic changes and neuropathic pain in APN through inhibiting the oxidative stress and inflammatory cytokine levels in the sciatic nerve. These findings provide rationale and experimental evidence for the development of Res therapeutic strategy to alleviate APN.
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