Succinate dehydrogenase in Parkinson＇s disease

BACKGROUND： The prevalence of neurodegenerative disorders such as Parkinson＇s disease （PD） is increased by age. Alleviation of their symptoms and protection of normal neurons against degeneration are the main aspects of the researches to establish novel therapeutic strategies. Many studies have shown that mitochondria as the most important organelles in the brain which show impairment in PD models. Succinate dehydrogenase （SDH） as a component of the oxidative phosphorylation system in mitochondria connects Krebs cycle to the electron transport chain. Dysfunction or inhibition of the SDH can trigger mitochondrial impairment and disruption in ATP generation. Excessive in lipid synthesis and induction of the excitotoxicity as inducers in PD are controlled by SDH activity directly and indirectly. On the other hand, mutation in subunits of the SDH correlates with the onset of neurodegenerative disorders. Therefore, SDH could behave as one of the main regulators in neuroprotection. OBJECTIVE： In this review we will consider contribution of the SDH and its related mechanisms in PD. METHODS： Pubmed search engine was used to find published studies from 1977 to 2016. ＂Succinate dehydrogenase＂, ＂lipid and brain＂, ＂mitochondria and Parkinson＇s disease＂ were the main keywords for searching in the engine. RESULTS： Wide ranges of studies （59 articles） in neurodegenerative disorders especially Parkinson＇s disease like genetics of the Parkinson＇s disease, effects of the mutant SDH on cell activity and physiology and lipid alteration in neurodegenerative disorders have been used in this review. CONCLUSION： Mitochondria as key organelles in the energy generation plays crucial roles in PD. ETC complex in this organelle consists four complexes which alteration in their activities cause ROS generation and ATP depletion. Most of complexes are encoded by mtDNA while complex Ⅱ is the only part of the ETC which is encoded by nuclear genome. So, focusing on the SDH and related pathways which have important role in neuronal survival and SDH has a potential to further studies as a novel neuroproteetive agent.

Intestinal Dopamine Receptor D2 is Required for Neuroprotection Against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Dopaminergic Neurodegeneration

A wealth of evidence has suggested that gastrointestinal dysfunction is associated with the onset and progression of Parkinson’s disease(PD).However,the mechanisms underlying these links remain to be defined.Here,we investigated the impact of deregulation of intestinal dopamine D2 receptor(DRD2)signaling in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced dopaminergic neurodegeneration.Dopamine/dopamine signaling in the mouse colon decreased with ageing.Selective ablation of Drd2,but not Drd4,in the intestinal epithelium,caused a more severe loss of dopaminergic neurons in the substantia nigra following MPTP challenge,and this was accompanied by a reduced abundance of succinate-producing Alleoprevotella in the gut microbiota.Administration of succinate markedly attenuated dopaminergic neuronal loss in MPTP-treated mice by elevating the mitochondrial membrane potential.This study suggests that intestinal epithelial DRD2 activity and succinate from the gut microbiome contribute to the maintenance of nigral DA neuron survival.These findings provide a potential strategy targeting neuroinflammation-related neurological disorders such as PD.

Mitochondrial neuronal uncoupling proteins:a target for potential disease-modification in Parkinson’s disease Philip

This review gives a brief insight into the role of mitochondrial dysfunction and oxidative stress in the converging pathogenic processes involved in Parkinson’s disease(PD).Mitochondria provide cellular energy in the form of ATP via oxidative phosphorylation,but as an integral part of this process,superoxides and other reactive oxygen species are also produced.Excessive free radical production contributes to oxidative stress.Cells have evolved to handle such stress via various endogenous anti-oxidant proteins.One such family of proteins is the mitochondrial uncoupling proteins(UCPs),which are anion carriers located in the mitochondrial inner membrane.There are five known homologues(UCP1 to 5),of which UCP4 and 5 are predominantly expressed in neural cells.In a series of previous publications,we have shown how these neuronal UCPs respond to 1-methyl-4-phenylpyridinium(MPP+;toxic metabolite of MPTP)and dopamine-induced toxicity to alleviate neuronal cell death by preserving ATP levels and mitochondrial membrane potential,and reducing oxidative stress.We also showed how their expression can be influenced by nuclear factor kappa-B(NF-
B)signaling pathway specifically in UCP4.Furthermore,we previously reported an interesting link between PD and metabolic processes through the protective effects of leptin(hormone produced by adipocytes)acting via UCP2 against MPP+-induced toxicity.There is increasing evidence that these endogenous neuronal UCPs can play a vital role to protect neurons against various pathogenic stresses including those associated with PD.Their expression,which can be induced,may well be a potential therapeutic target for various drugs to alleviate the harmful effects of pathogenic processes in PD and hence modify the progression of this disease.

基于CaMkkβ/AMPK通路介导线粒体自噬探讨敛肝熄风止颤方的神经保护机制

目的:观察敛肝熄风止颤方对帕金森病(Parkinson Disease,PD)的影响,探讨其神经保护机制。方法:将60只SD大鼠分为假手术组10只,造模组50只,造模组大鼠接受PD模型制备,将成模的40只大鼠随机分为模型组10只、低剂量组(0.36 g/kg)10只、中剂量组(0.72 g/kg)及高剂量组(1.44 g/kg)10只,持续灌胃给药30 d,比较各组大鼠阿扑吗啡诱导旋转次数、圆筒实验,纹状体超微结构以及CaMkkβ、AMPK、p-AMPK水平的变化。结果:1)敛肝熄风止颤方可明显减少大鼠转圈以及肢体碰壁的次数,随着剂量增加次数减少更明显,差异有统计学意义(P<0.05)。2)造模大鼠纹状体线粒体自噬现象减弱,敛肝熄风止颤方可明显促进脑组织线粒体自噬。3)中药干预后大鼠纹状体CaMkkβ、p-AMPK蛋白表达上调,与模型组比较,差异有统计学意义(P<0.05),其中高剂量组较低剂量组上调明显,差异有统计学意义(P<0.05)。结论:敛肝熄风止颤方对帕金森病具有神经保护作用,其机制之一可能是通过激活CaMkk/AMPK通路活性促进线粒体自噬有关。

普拉克索片对帕金森病细胞模型的线粒体保护作用

目的研究普拉克索片对帕金森病(PD)细胞模型的线粒体保护作用。方法 PC12细胞经0.16 nmol·L^(-1)1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)作用48 h建立PD细胞模型,低、中、高剂量实验组分别加入0.50×10-1,0.10,0.50 mmol·L^(-1)普拉克索片,模型组加等量生理盐水,另设正常PC12细胞为对照组。以溴化四唑蓝比色(MTT)法检测细胞增殖,以荧光标记和偏振法检测细胞线粒体膜流动性、膜电位,以蛋白免疫印迹法检测凋亡相关蛋白表达。结果低剂量实验组培养24,48 h细胞存活率分别为(73.47±3.63)%,(72.65±3.17)%,均高于模型组的(54.35±3.67)%,(52.17±2.65)%。低剂量实验组细胞线粒体膜荧光偏振度、微黏度、相对荧光强度分别为(0.53±0.06)Pola,(3.23±0.53)P·s-1,503.25±45.67,模型组分别为(0.64±0.15)Pola,(5.87±1.36)P·s-1,369.87±33.26,差异均有统计学意义(均P<0.05)。与模型组相比,实验组细胞存活率升高,且随普拉克索片作用浓度的升高呈逐渐升高趋势(P<0.01)。与对照组比较,模型组细胞线粒体膜荧光偏振度和微黏度升高,膜电位降低(P<0.01);实验组随普拉克索片干预浓度的增大线粒体膜荧光偏振度和微黏度逐渐降低,膜电位逐渐升高,且与模型组相比差异有统计学意义(P<0.05或P<0.01)。对照组、模型组和实验组PC12细胞胱天蛋白酶-3(Caspase-3)蛋白相对表达量分别为0.36±0.11,0.58±0.19,0.41±0.08,0.39±0.09,0.35±0.09;与对照组比较,模型组Caspase-3蛋白相对表达量升高(P<0.05),与模型组比较,实验组Caspase-3蛋白相对表达量降低,且随普拉克索作用浓度增加呈逐渐降低趋势(P<0.05)。结论普拉克索片可促进PD模型细胞增殖,同时可改善细胞线粒体结构与功能,进而起到抗细胞凋亡的保护作用。