Molecular pathways of neurodegeneration in Parkinson's disease

Parkinson's disease (PD) is a complex disorder with many different causes, yet they may intersect in common pathways, raising the possibility that neuroprotective agents may have broad applicability in the treatment of PD. Current evidence suggests that mitochondrial complex I inhibition may be the central cause of sporadic PD and that derangements in complex I cause alpha-synuclein aggregation, which contributes to the demise of dopamine neurons. Accumulation and aggregation of alpha-synuclein may further contribute to the death of dopamine neurons through impairments in protein handling and detoxification. Dysfunction of parkin (a ubiquitin E3 ligase) and DJ-1 could contribute to these deficits. Strategies aimed at restoring complex I activity, reducing oxidative stress and alpha-synuclein aggregation, and enhancing protein degradation may hold particular promise as powerful neuroprotective agents in the treatment of PD.     

D1 dopamine receptor activation required for postsynaptic expression of D2 agonist effects

D1 and D2 dopamine receptors exert synergistic effects on the firing rates of basal ganglia neurons and on the expression of stereotyped behavior in rats. Moreover, the ability of D2 agonists to induce changes in basal ganglia single unit activity and spontaneous motor activity is dependent upon the presence of endogenous dopamine to stimulate D1 receptors; in rats treated with alpha-methyl-rho-tyrosine to reduce endogenous dopamine levels, the neurophysiological and behavioral effects of the D2 agonist quinpirole are significantly attenuated, while the effects of nonselective agonists like apomorphine, which stimulate both D1 and D2 receptors, or combinations of a D2 agonist and a D1 agonist are not attenuated. Thus, the previously held view that D2 receptors alone are responsible for evoking the changes in behavior and basal ganglia output induced by nonselective dopamine agonists and endogenous dopamine is not supported by these results, which indicate that these phenomena require concurrent stimulation of both dopamine receptor subtypes.     

σ-共核蛋白在帕金森疾病中的功能

介绍了σ-共核蛋白的来源、结构,分析了对帕金森疾病有关键作用的多巴胺合成方面的σ-共核蛋白的调节作用,并探讨了σ-共核蛋白如何发生聚集及发生聚集后可能会造成PD的发生,最后重点讨论了σ-共核蛋白引起PD的多巴胺能神经元变性的作用。     

S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function

Parkin is an E3 ubiquitin ligase involved in the ubiquitination of proteins that are important in the survival of dopamine neurons in Parkinson's disease (PD). We show that parkin is S-nitrosylated in vitro, as well as in vivo in a mouse model of PD and in brains of patients with PD and diffuse Lewy body disease. Moreover, S-nitrosylation inhibits parkin's ubiquitin E3 ligase activity and its protective function. The inhibition of parkin's ubiquitin E3 ligase activity by S-nitrosylation could contribute to the degenerative process in these disorders by impairing the ubiquitination of parkin substrates.     

帕金森病模型大鼠脑内CDNF表达变化

为了探讨帕金森病(PD)发病过程中大脑多巴胺能神经营养因子(CDNF)表达的变化,以大鼠为模型,研究了帕金森病CDNF及相关基因的表达变化,从而为基因治疗帕金森病提供理论依据。实验采用单侧黑质内单点注射6-羟多巴胺的方法制备帕金森病大鼠模型;运用免疫组织化学、Western blot及Q-PCR方法检测CDNF和多巴胺合成限速酶—酪氨酸羟化酶(TH)在模型大鼠黑质中表达的变化。研究结果发现,PD模型大鼠脑黑质区CDNF和TH阳性细胞数明显减少;进一步研究表明,与正常大鼠相比,模型大鼠CDNF m RNA表达水平虽未见显著改变(P0.05),但CDNF及TH蛋白表达极显著降低(P0.01)。提示帕金森病的发病可能与黑质中CDNF和TH表达量降低,进而抑制多巴胺合成有关。     

Biomedicine. Combating Parkinson's disease--step three

The degeneration of dopamine neurons in the nigrostriatal pathway of the brain results in the debilitating motor deficits of Parkinson's disease. In a Perspective, Olson discusses a new study (Kordower et al.) demonstrating that injection of a lentiviral vector containing the gene encoding GDNF (a trophic factor for dopamine neurons) into the nigrostriatal pathway of monkeys with PD prevents neuronal loss and reverses some of the motor deficits of this disease.     

Placebo and opioid analgesia-- imaging a shared neuronal network

It has been suggested that placebo analgesia involves both higher order cognitive networks and endogenous opioid systems. The rostral anterior cingulate cortex (rACC) and the brainstem are implicated in opioid analgesia, suggesting a similar role for these structures in placebo analgesia. Using positron emission tomography, we confirmed that both opioid and placebo analgesia are associated with increased activity in the rACC. We also observed a covariation between the activity in the rACC and the brainstem during both opioid and placebo analgesia, but not during the pain-only condition. These findings indicate a related neural mechanism in placebo and opioid analgesia.     

Opioid inhibition of dopamine release from nervous tissue of Mytilus edulis and Octopus bimaculatus

Morphine and D-Ala2-Met-enkephalin as well as other opioids suppress potassium-stimulated release of 3H-labeled dopamine from neurons tissue of two marine invertebrates, Mytilus edulis and Octopus bimaculatus. Naloxone reverses the inhibitory effects in both species. Potassium-stimulated release of 3H-labeled serotonin is not altered by opioids. It is postulated that opiate receptors and their endogenous effectors play a prominent role in regulation of transmitter release in invertebrates.     

L-Dopa-induced release of cerebral monoamines

L-Dopa markedly increased the efflux of tritiated dopamine and tritiated serotonin from rat brain slices. This action appeared contingent on the decarboxylation of L-dopa to dopamine, since it could be blocked by an inhibitor of L-amino acid decarboxylase. Selective destruction of catecholamine-containing nerve terminals by 6-hydroxydopamine significantly decreased the uptake and release of tritiated dopamine but not that of tritiated serotonin. These observations support the hypothesis that a portion of exogenously administered L-dopa may enter central serotonin terminals and undergo decarboxylation to the amine with resultant displacement of the endogenous indoleamine from vesicular stores.     

Subthalamic GAD gene therapy in a Parkinson's disease rat model

The motor abnormalities of Parkinson's disease (PD) are caused by alterations in basal ganglia network activity, including disinhibition of the subthalamic nucleus (STN), and excessive activity of the major output nuclei. Using adeno-associated viral vector-mediated somatic cell gene transfer, we expressed glutamic acid decarboxylase (GAD), the enzyme that catalyzes synthesis of the neurotransmitter GABA, in excitatory glutamatergic neurons of the STN in rats. The transduced neurons, when driven by electrical stimulation, produced mixed inhibitory responses associated with GABA release. This phenotypic shift resulted in strong neuroprotection of nigral dopamine neurons and rescue of the parkinsonian behavioral phenotype. This strategy suggests that there is plasticity between excitatory and inhibitory neurotransmission in the mammalian brain that could be exploited for therapeutic benefit.     

水稻盐粳187的群体植伤研究

给出了用于度量水稻群体植伤的一组指标；植伤持续期，植伤强度和相对植伤势。分析了栽插密度，施用N素对盐粳187群体植伤的影响。结果表明，栽插密度对盐粳187群体植伤影响不显著，而施用N素则对群体植伤有显著影响。     

Dopamine synthesis: stimulation by a hypothalamic factor

The effect of treatment with the factor that inhibits the release of melanocyte stimulating hormone (MSH) identified as 1-prolyl-1-leucylglycinamide (MIF) on brain catecholamine synthesis was examined in normal and hypophysectomized rats. The tripeptide induced a dose-related increase in striatal dopamine synthesis in slices obtained from treated normal animals but not in hypophysectomized animals. Hypothalamic norepinephrine synthesis was unaltered by MIF treatment in normal as well as in hypophysectomized rats. In addition, dopamine and norepinephrine syntheses were depressed in untreated hypophysectomized animals, as compared to normal controls. These results constitute the first direct demonstration of a central neurochemical effect of a hypothalamic factor.     

中药方剂白头翁汤抗细菌内毒素的作用研究

探讨中药方剂白头翁汤对细菌内毒素（LPS）的治疗和预防作用,取中药饮片按常规方法煎制成生药质量浓度为1g/mL的白头翁汤药液。分高（1g/mL）、中（0.5g/mL）、低（0.1g/mL）3个剂量给小鼠灌胃,每天1次,连续5d。第1次给药前3h和最后1次给药后3h分别腹腔注射LPS（9mg/kg）。记录LPS攻毒后48h内小鼠的死亡率,同时测定各组小鼠的体重、血液指标及器官指数。结果显示,预防高剂量组的小鼠死亡率极显著低于LPS对照组,差异极显著,治疗高剂量组和预防中剂量组显著低于LPS对照组,差异显著。治疗高剂量组和预防高剂量组的小鼠体重在24h时显著高于LPS对照组,差异显著。治疗高剂量组的小鼠白细胞数目、血红蛋白浓度、平均血红蛋白和血小板升高数量较LPS对照组均差异显著。治疗高剂量组小鼠的肝脏、脾脏和肠管指数显著低于LPS对照组,均差异显著。表明中药方剂白头翁汤具有明显的抗大肠杆菌内毒素作用。     

鱼类内源消化酶系改性豆粕工艺初探

[目的]探索鱼类内源酶系对豆粕中大豆抗原蛋白的降解效果,为建立鱼内脏改性豆粕体系提供理论依据。[方法]采用SDS-PAGE电泳分析方法初步考察了初始pH、前处理条件、鱼类品种对鱼类内源复合酶系对豆粕中大豆抗原蛋白降解的影响。[结果]在50℃酶解温度下,初始pH 4.0条件下酶解效果最佳,其次为初始自然pH条件,初始中性和碱性条件下酶解效果不佳;加热前处理对酶解过程有明显促进作用,80～100℃范围内,随前处理温度升高,对酶解的促进逐渐加强;在自然pH环境及50℃酶解温度条件下,带鱼内源消化酶系酶解豆粕的效果明显比花鲢和鳗鱼内源酶系酶解豆粕的效果强,其中鳗鱼内源酶系的酶解作用相对较弱。[结论]研究显示,鱼类内源消化酶是一种潜在的豆粕抗营养因子改性酶原料。     

内源激素对水稻不同外植体培养力的影响

利用HPLC法对愈伤组织诱导率和绿苗分化率有差异的几个水稻品种的不同外植体(花药、幼穗、幼胚和成熟胚)及其愈伤组织的内源激素含量进行测定分析。结果表明,内源激素的含量和配比是影响愈伤组织诱导和绿苗分化的关键因素之一。不同外植体中的内源激素对愈伤组织诱导率的表现为:Z ZR呈负效应,IAA呈正效应,GA除成熟胚外呈负效应。愈伤组织中内源激素对绿苗分化率的影响表现为:IAA和GA呈负效应,ABA、Z ZR呈正效应。内源激素的配比对愈伤组织诱导率和绿苗分化率有一定作用,表现为:IAA/Z ZR对愈伤组织诱导率有一定的正效应,Z ZR/IAA、ABA/IAA对绿苗分化率呈显著正相关。     

Hereditary early-onset Parkinson's disease caused by mutations in PINK1

Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. We previously mapped a locus for a rare familial form of PD to chromosome 1p36 (PARK6). Here we show that mutations in PINK1 (PTEN-induced kinase 1) are associated with PARK6. We have identified two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families: a truncating nonsense mutation and a missense mutation at a highly conserved amino acid. Cell culture studies suggest that PINK1 is mitochondrially located and may exert a protective effect on the cell that is abrogated by the mutations, resulting in increased susceptibility to cellular stress. These data provide a direct molecular link between mitochondria and the pathogenesis of PD.     

Dopamine protects mice against whole-body irradiation

Injection of dopamine before whole-body x-irradiation of mice resulted in 80 percent survivors whereas no irradiated controls survived; injection after exposure had no effect. D,L-Dihydroxyphenylalanine, the precursor of dopamine, had no effect on survival when injected either before or after irradiation.     

白桦组培再生系统的研究（Ⅲ）——组培过程中内源激素的变化

为了探讨白桦（ＢｅｔｕｌａｐｌａｔｙｐｈｙｌｌａＳｕｋｓ）组织培养的繁殖机理,选取白桦组织培养过程中的不同材料,采用间接酶联免疫吸附地,研究了不同发育阶段,部位及无性系的植物内洙激素含量的变化,以及加入不同的外源激素对内源激素的影响,探讨了芽,根的分化与内,外源激素的变化,结果表明：（１）ＩＡＡ是愈伤组织生长的重要内部因子,（２）ＧＡ和ＩＡＡ共同作用促进愈伤组织的生长;（３）不同无性系的ＩＡＡ含量     

Facilitation of brain self-stimulation by central administration of norepinephrine

Rats with electrodes implanted in the medial forebrain bundle stimulated their own brains at sharply reduced rates after systemic administration of disulfiram or intraventricular administration of diethyldithiocarbamate. Both drugs inhibit dopamine-beta-hydroxylase, the enzyme responsible for the final step in the biosynthesis of norepinephrine. The suppressed behavior was reinstated by intraventricular injections of 1-norepinephrine, but not by injection of its biologically inactive isomer, d-norepinephrine. Intraventricular administration of dopamine and serotonin did not restore self-stimulation. The rewarding effect of medial forebrain bundle stimulation may depend on the availability of norepinephrine as a transmitter, but not on dopamine or serotonin.     

The Influence of Endogenous Hormones on Culture Capability of Different Explants in Rice

The endogenous hormones (EHs) content of different explants (anther, young panicle, young embryo and mature embryo)and calli with different culture capability were analyzed by means of high performance liquid chromatography (HPLC). The results showed that the contents and ratio of endogenous hormones were one of the key factors affecting callus induction frequencies (CIF) and green plantlet differentiation frequencies (GPDF). The influence of endogenous hormones of different explants on CIF represented as: Zoatin ribosile (ZR) showed negative effect, indole-3-acetic acid (IAA) did positive effect, and gibberellic acid (GA) did negative effect except for mature embryos. The influence of endogenous hormones on green plantlet differentiation frequency (GPDF) showed: IAA and GA were negative effect; abscisic acid (ABA) and zeatin+ zeatin riboside (Z+ZR) were positive effect. The mixture ratio of endogenous hormones played a role on CIF and GPDF. IAA/Z+ZR had a positive effect on CIF, and there was a notable positive correlation between Z+ZR/IAA and GPDF, so was between ABA/IAA and GPDF.