神经干细胞向多巴胺能神经元分化机制的研究进展

帕金森病是中脑黑质的多巴胺能神经元缺失引起的慢性中枢神经系统功能失调。目前,应用神经干细胞在体内外分化成多巴胺能神经元是帕金森病细胞替代治疗的重要途径。本文综合近十年来的研究进展,对神经干细胞向多巴胺能神经元分化过程中重要的分子机制、信号通路以及外界影响因素进行综述。     

炎症在帕金森病中的作用

帕金森病是中老年人常见的神经变性疾病,以黑质致密部多巴胺能神经元进行性缺失、纹状体多巴胺水平降低为主要特点。中枢神经系统炎症和全身炎症都会导致多巴胺能神经元变性和死亡;抑制中枢神经炎症,靶向调节全身炎症、减轻外周损伤对大脑的影响,有助于缓解和阻止病情的发展,给帕金森病的预防和治疗提供新思路。     

小鼠耳肿胀模型及药理应用

炎症是损伤和抗损伤的统一过程.尽管炎性反应过程中,通过实质和间质细胞的再生使受损的组织得以修复和愈合,但损伤因子直接或间接造成组织和细胞的破坏,也会给机体带来损伤.目前的抗炎药物仍存在许多问题,如选择性较差、会引起胃肠道不适、肾衰竭和心功能衰竭等副作用.因此寻找安全有效的抗炎药物,以及选择合适的动物模型评价抗炎药物的药效和机制仍是众多学者共同关注的问题.     

细胞移植治疗帕金森病的研究及进展

<正>上世纪90年代以来,随着细胞生物学研究的深入,神经细胞移植技术已日益引起人们的广泛关注。由于帕金森病(PD)的病理机制比较明确,是黑质中的多巴胺能神经元以及     

α-硫辛酸在帕金森病中的神经保护作用研究

正帕金森病(PD)是以多巴胺(DA)能神经元慢性、进行性缺失、死亡为特征的神经变性疾病,由此引起黑质-纹状体内多巴胺能神经递质耗竭而致病。尽管PD发病机理尚未阐明,但大量研究证实氧化应激、线粒体异常、及神经炎症等在PD的发生、发展中起重要作用,故此抗氧化应激、保护线粒体、抗神经炎症,从而来减缓PD恶化有重大意义。α-硫辛酸(ALA)具有     

帕金森病的病理生理研究进展

1引言 帕金森病是一种常见于中老年人的中枢神经系统变性疾病,以震颤、肌僵直和运动减少为典型临床表现,其病因和发病机制至今仍不太明确,主要病理改变为黑质纹状体多巴胺神经元进行性变性、死亡,同时伴随含嗜酸性包涵体(lewy小体)出现,纹状体多巴胺含量降低,引起运动功能紊乱.帕金森病发病的病理生理机制中,主要存在氧化应激反应、线粒体功能缺陷、兴奋性毒性损害等因素,它们可能通过不同途径影响神经细胞的信号传导和信息传递,最终导致多巴胺神经元发生细胞凋亡,现将主要研究进展简要介绍如下.     

帕金森病的干细胞治疗进展

传统帕金森病的治疗方法主要有药物治疗和外科治疗,近来发展较快的治疗方法则包括干细胞移植及基因治疗等.用于治疗帕金森病的干细胞有胚胎干细胞、神经干细胞、间充质干细胞,干细胞移植在帕金森病动物模型和临床上都取得了一定的治疗成果,干细胞联合基因治疗也取得了较好的研究结果.干细胞移植治疗帕金森病的机制主要有替代作用、对多巴胺能神经元的保护及营养作用及促进内源性多巴胺能神经元的发生,但干细胞来源的多巴胺能神经无移植后能否存活、恢复纹状体的神经支配、移植干细胞的远期疗效等还有待于进一步证明.     

帕金森病伴发抑郁的发病机制及其干预

抑郁是帕金森病(PD)最常见的非运动症状,严重影响患者的生活质量。本文从多巴胺、5-羟色胺和去甲肾上腺素等神经生物学以及内因性因素方面,探讨帕金森病伴发抑郁的发病机制。并从中西医的角度综述对帕金森病伴发抑郁的临床干预。     

miR-137基因与帕金森病的相关性研究进展

帕金森病（parkinson’s disease, PD）是一种中老年人常见的神经退行性疾病,其病理特征是多巴胺能神经元的进行性损伤和缺失及神经元中路易氏体的形成,其中关于神经元缺失的理论包括线粒体功能障碍、炎症、蛋白质的异常和氧化应激。微小RNA-137(miR-137)是一种小的非编码调控RNA,在神经、精神系统疾病的发病机制中也发挥着重要作用。有研究表明miR-137在帕金森病患者的表达异常,并且可能与帕金森病的线粒体功能障碍、蛋白质的异常相关。进一步探究miR-137与帕金森病的关系对于帕金森病的发病机制具有重要意义,可能为帕金森病的治疗提供新方向。     

The lipopolysaccharide Parkinson's disease animal model: mechanistic studies and drug discovery

Research in the last two decades has unveiled an important role for neuroinflammation in the degeneration of the nigrostriatal dopaminergic (DA) pathway that constitutes the pathological basis of the prevailing movement disorder, Parkinson's disease (PD). Neuroinflammation is characterized by the activation of brain glial cells, primarily microglia and astrocytes that release various soluble factors that include free radicals (reactive oxygen and nitrogen species), cytokines, and lipid metabolites. The majority of these glia-derived factors are proinflammatory and neurotoxic and are particularly deleterious to oxidative damage-vulnerable nigral DA neurons. As a proof of concept, various immunologic stimuli have been employed to directly induce glial activation to model DA neurodegeneration in PD. The bacterial endotoxin, lipopolysaccharide (LPS), has been the most extensively utilized glial activator for the induction of inflammatory DA neurodegeneration. In this review, we will summarize the various in vitro and in vivo LPS PD models. Furthermore, we will highlight the contribution of the LPS PD models to the mechanistic studies of PD pathogenesis and the search for neuroprotective agents for the treatment of PD.     

Inflammatory process in Parkinson disease: neuroprotection by neuropeptide Y

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the nigro‐striatal pathway. Interestingly, it has already been shown that an intracerebral administration of neuropeptide Y (NPY) decreases the neurodegeneration induced by 6‐hydroxydopamine (6‐OHDA) in rodents and prevents loss of dopamine (DA) and DA transporter density. The etiology of idiopathic PD now suggest that chronic production of inflammatory mediators by activated microglial cells mediates the majority of DA‐neuronal tissue destruction. In an animal experimental model of PD, the present study shows that NPY inhibited the activation of microglia evaluated by the binding of the translocator protein (TSPO) ligand [3H]PK11195 in striatum and substantia nigra of 6‐OHDA rats. These results suggest a potential role for inflammation in the pathophysiology of the disease and a potential treatment by NPY in PD.     

Mechanism of specific dopaminergic neuronal death in Parkinson's disease

Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic (DAergic) neurons of the nigrostriatal system, with resulting reduction in striatal dopamine (DA) concentration. Various mechanisms have been implicated in the pathogenesis and progression of PD. Among them, mitochondrial dysfunction, inflammation and oxidative stress had been accepted as the most plausible mechanism of disease progression. The free radicals/oxidative stress produced by MPTP, 6-hydroxydopamine, rotenone, activated microglias, and disturbances in mitochondrial respiratory enzymes provide a common pathway for the progression of all kinds of neurons. On the other hand, numerous studies on DA-induced neurotoxicity have been reported recently, and DA itself exerts cytotoxicity in DAergic neurons mainly due to the generation of highly reactive DA -quinones which are DAergic neuron-specific cytotoxic molecules. DA quinones may irreversibly alter protein function through the formation 5-cysteinyl-dopamine on the protein. For example, the formation of DA quinone-alpha-synuclein complex consequently increases cytotoxic protofibrils and covalent modification of functional enzymes. Thus, DA quinones play an important role in 'specific' DAergic neuro-degeneration of PD.     

Delayed Dominant-Negative TNF Gene Therapy Halts Progressive Loss of Nigral Dopaminergic Neurons in a Rat Model of Parkinson's Disease

Parkinson''s disease (PD) is a progressive neurodegenerative disorder typified by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Recent evidence indicates that neuroinflammation may play a critical role in the pathogenesis of PD, particularly tumor necrosis factor (TNF). We have previously shown that soluble TNF (solTNF) is required to mediate robust degeneration induced by 6-hydroxydopamine (6-OHDA) or lipopolysaccharide. What remains unknown is whether TNF inhibition can attenuate the delayed and progressive phase of neurodegeneration. To test this, rats were injected in the SNpc with lentivirus encoding dominant-negative TNF (lenti-DN-TNF) 2 weeks after receiving a 6-OHDA lesion. Remarkably, when examined 5 weeks after the initial 6-OHDA lesion, no further loss of nigral DA neurons was observed. Lenti-DN-TNF also attenuated microglial activation. Together, these data suggest that TNF is likely a critical mediator of nigral DA neuron death during the delayed and progressive phase of neurodegeneration, and that microglia may be the principal cell type involved. These promising findings provide compelling reasons to perform DN-TNF gene transfer studies in nonhuman primates with the long-term goal of using it in the clinic to prevent the delayed and progressive degeneration of DA neurons that gives rise to motor symptoms in PD.     

Effect of (R)-salsolinol and N-methyl-(R)-salsolinol on the balance impairment between dopamine and acetylcholine in rat brain: involvement in pathogenesis of Parkinson disease

BACKGROUND: Parkinson disease (PD), a progressive neurodegenerative disease, affects at least 1% of population above the age of 65. Although the specific etiology of PD remains unclear, recently the endogenous neurotoxins such as (R)-salsolinol [(R)-Sal] and N-methyl-(R)-salsolinol [(R)-NMSal] have been thought to play a major role in PD. Much interest is focused on the degeneration of dopamine neurons induced by these neurotoxins. However, little literature is available on the impact of endogenous neurotoxins on the balance between dopamine (DA) and acetylcholine (ACh). METHODS: After injection of (R)-Sal or (R)-NMSal into the rat brain striatum, the concentrations of DA and its metabolites were detected by HPLC with electrochemical detection. We assessed the influence of neurotoxins on acetylcholinesterase (AChE) activity and developed a microdialysis-electrochemical device to measure ACh concentrations with enzyme-modified electrodes. RESULTS: (R)-Sal and (R)-NMSal led to concentration-dependent decreases in the activity of AChE. ACh concentrations in striatum treated with (R)-Sal or (R)-NMSal were increased to 131.7% and 239.8% of control, respectively. As to the dopaminergic system, (R)-NMSal caused a significant decrease in DA concentrations and (R)-Sal reduced the concentrations of DA metabolites in the striatum. CONCLUSIONS: (R)-Sal and (R)-NMSal exerted a considerable effect on the balance between DA and ACh by impairing the cholinergic system as well as the dopaminergic system. It is likely that the disruption of balance between DA and ACh plays a critical role in the pathogenesis of neurotoxin-induced PD.     

Colon-specific delivery of prednisolone-appended alpha-cyclodextrin conjugate: alleviation of systemic side effect after oral administration.

Prednisolone (PD), a typical glucocorticoid, has been widely used for the treatment of inflammatory bowel disease (IBD). However, when PD is administered orally, a large amount of the drug is absorbed from the upper gastrointestinal (GI) tract and causes systemic side effects. In this study, the anti-inflammatory effect and systemic side effect of the PD succinate/alpha-cyclodextrin (PDsuc/alpha-CyD) ester conjugate after oral administration were studied using IBD model rats. The anti-inflammatory effect of the PDsuc/alpha-CyD conjugate was comparable to those of PD alone. On the other hand, the systemic side effect of the PDsuc/alpha-CyD conjugate was much lower than that of PD alone when administered orally. The lower side effect of the conjugate was attributable to passage of the conjugate through the stomach and small intestine without significant degradation or absorption, followed by the degradation of the conjugate site-specifically in the large intestine. The oral administration of PD alone gave higher plasma concentrations of PD, giving the significant systemic side effect. The results suggested that the PDsuc/alpha-CyD conjugate is useful as a delayed-release type prodrug of PD for colon-specific delivery, owing to alleviation of the systemic side effect, while maintaining the therapeutic effect.     

Protective effect of sulforaphane against dopaminergic cell death

Parkinson's disease (PD) is a progressive neurodegenerative disorder with a selective loss of dopaminergic neurons in the substantia nigra. Evidence suggests oxidation of dopamine (DA) to DA quinone and consequent oxidative stress as a major factor contributing to this vulnerability. We have previously observed that exposure to or induction of NAD(P)H:quinone reductase (QR1), the enzyme that catalyzes the reduction of quinone, effectively protects DA cells. Sulforaphane (SF) is a drug identified as a potent inducer of QR1 in various non-neuronal cells. In the present study, we show that SF protects against compounds known to induce DA quinone production (6-hydroxydopamine and tetrahydrobiopterin) in DAergic cell lines CATH.a and SK-N-BE(2)C as well as in mesencephalic DAergic neurons. SF leads to attenuation of the increase in protein-bound quinone in tetrahydrobiopterin-treated cells, but this does not occur in cells that have been depleted of DA, suggesting involvement of DA quinone. SF pretreatment prevents membrane damage, DNA fragmentation, and accumulation of reactive oxygen species. SF causes increases in mRNA levels and enzymatic activity of QR1 in a dose-dependent manner. Taken together, these results indicate that SF causes induction of QR1 gene expression, removal of intracellular DA quinone, and protection against toxicity in DAergic cells. Thus, this major isothiocyanate found in cruciferous vegetables may serve as a potential candidate for development of treatment and/or prevention of PD.     

Gene therapy for Parkinson's disease

Recent advances in gene transfer methods, especially development of a high titer recombinant adeno-associated viral (AAV) vector, are making gene therapy for Parkinson's disease (PD) a feasible therapeutic option in the clinical arena. Efficient and long-term expression of genes for dopamine (DA)-synthesizing enzymes in the striatum restored local DA production and allowed behavioral recovery in animal models of PD. Moreover, sustained expression of a glial cell line-derived neurotrophic factor gene in the striatum rescued nigral neurons and led to functional recovery in a rat model of PD, even when treatment was delayed until after the onset of progressive degeneration. A clinical trial to evaluate the efficacy of subthalamic transduction to produce inhibitory transmitters is underway.     

Pharmacological characterization of PD 118717, a putative piperazinyl benzopyranone dopamine autoreceptor agonist.

PD 118717 (7-[3-[4-(2-pyrimidinyl)-1-piperazinyl]-propoxy]-2H-1- benzopyran-2-one sulfate) proved to be a dopamine (DA) D-2 autoreceptor agonist in biochemical and electrophysiological studies in rats and to exhibit an antipsychotic-like profile in behavioral tests in rodents and monkeys. In vitro binding studies indicated that PD 118717 bound selectively to DA D-2 vs. D-1 receptors and exhibited agonist binding properties (biphasic inhibitory curves and GTP shift) similar to DA. It also had significant affinity for serotonin-(5-HT)1A but not 5-HT1B and 5-HT2 receptors. PD 118717 was active in antagonizing the tau-butyrolactone-induced accumulation of dopa in rat striatum and mesolimbic regions. PD 118717 also depressed the firing of DA neurons in substantia nigra pars compacta of rats. In both of the latter tests the effects of PD 118717 were reversed by haloperidol. PD 118717 decreased brain DA metabolism, decreased DA utilization, decreased accumulation of dopa after inhibition of L-aromatic amino acid decarboxylase, stimulated serum corticosterone and inhibited stimulated serum prolactin levels. PD 118717 did not alter striatal acetylcholine levels; nor did it induce locomotor stimulation or stereotypy in normal animals, suggesting a lack of postsynaptic DA stimulation of normosensitive DA receptors. In tests designed to reveal even weak postsynaptic DA agonist effects, PD 118717 stimulated locomotor activity in 6-hydroxydopamine-lesioned animals and relatively higher doses induced a low degree of stereotyped behavior when combined with the DA D-1 agonist SKF 38393. PD 118717 decreased the accumulation of 5-hydroxytryptophan in brain, an effect probably due to an agonist action at 5-HT1A receptors. PD 118717 decreased spontaneous locomotor activity in rodents, antagonized amphetamine-stimulated hyperactivity in mice and inhibited Sidman avoidance in monkeys, effects seen with antipsychotic agents. Unlike DA antagonist antipsychotics, PD 118717 did not induce extrapyramidal dysfunction in monkeys. PD 118717 displayed behavioral activity after p.o. dosing and its effects did not show tolerance on repeated dosing. In conclusion, PD 118717 has the profile of a DA autoreceptor agonist in neurochemical and neurophysiological tests and produces effects suggestive of antipsychotic efficacy without neurological side effect liability in preclinical behavioral tests.     

ES cell therapy for Parkinson's disease

Neural transplantation, as a treatment for advanced Parkinson's disease (PD), has been studied for more than a decade due to the potential replacement of degenerated dopaminergic (DA) neurons. Several open-label studies on implantation of fetal nigral neurons revealed improvement in motor functions. However, the benefits were incomplete in double-blind trials. Progressive neural or embryonic stem (ES) cell research has raised hopes of creating novel cell replacement therapies for PD. DA neurons have been efficiently produced from primate ES cells in astrocyte-conditioned medium. Transplantation of neuronal stem cells derived from primate ES cells into a primate model of PD restored striatal DA function, suggesting ES cells are suitable donor cells.