Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Parkinson's disease (PD) is considered to be an aging-related neurodegeneration of catecholamine (CA) systems [typically A9 dopamine (DA) neurons in the substantia nigra and A6 noradrenaline (NA) neurons in the locus coeruleus]. The main symptom is movement disorder caused by a DA deficiency at the nerve terminals of fibers that project from the substantia nigra to the striatum. Most PD is sporadic (sPD) without any hereditary history. sPD is speculated to be caused by some exogenous or endogenous substances that are neurotoxic toward CA neurons, which toxicity leads to mitochondrial dysfunction and subsequent oxidative stress resulting in the programmed cell death (apoptosis or autophagy) of DA neurons. 2. Recent studies on the causative genes of rare familial PD (fPD) cases, such as alpha-synuclein and parkin, suggest that dysfunction of the ubiquitin-proteasome system (UPS) and the resultant accumulation of misfolded proteins and endoplasmic reticulum stress may cause the death of DA neurons. 3. Activated microglia, which accompany an inflammatory process, are present in the nigro-striatum of the PD brain; and they produce protective or toxic substances, such as cytokines, neurotrophins, and reactive oxygen or nitrogen species. These activated microglia may be neuroprotective at first in the initial stage, and later may become neurotoxic owing to toxic change to promote the progression toward the death of CA neurons.4. All of these accumulating evidences on sPD and fPD points to a hypothesis that multiple primary causes of PD may be ultimately linked to a final common signal-transduction pathway leading to programmed cell death, i.e., apoptosis or autophagy, of the CA neurons.
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PMID:Cellular and molecular mechanisms of Parkinson's disease: neurotoxins, causative genes, and inflammatory cytokines. 1682 25

Oxidative stress has been implicated as playing a role in neurodegenerative disorders, such as ischemic stroke, Alzheimer's, Huntington's, and Parkinson's disease. Persuasive evidences have shown that microglial-mediated oxidative stress contributes significantly to cell loss and accompanying cognitive decline characteristic of the diseases. Based on the facts that (i) levels of catalytically active myeloperoxidase are elevated in diseased brains and (ii) myeloperoxidase polymorphism is associated with the risk of developing neurodegenerative disorders, HOCl as a major oxidant produced by activated phagocytes in the presence of myeloperoxidase is therefore suggested to be involved in neurodegeneration. Its association with neurodegeneration is further showed by elevated level of 3-chlorotyrosine (bio-marker of HOCl in vivo) in affected brain regions as well as HOCl scavenging ability of neuroprotectants, desferrioxamine and uric acid. In this review, we will summary the current understanding concerning the association of HOCl and neuronal cell death where production of HOCl will lead to further formation of reactive nitrogen and oxygen species. In addition, HOCl also causes tissue destruction and cellular damage leading cell death.
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PMID:Chlorinative stress: an under appreciated mediator of neurodegeneration? 1695 71

Reactive oxygen species (ROS) and reactive nitrogen species (RNS, e.g. nitric oxide, NO(*)) are well recognised for playing a dual role as both deleterious and beneficial species. ROS and RNS are normally generated by tightly regulated enzymes, such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. Overproduction of ROS (arising either from mitochondrial electron-transport chain or excessive stimulation of NAD(P)H) results in oxidative stress, a deleterious process that can be an important mediator of damage to cell structures, including lipids and membranes, proteins, and DNA. In contrast, beneficial effects of ROS/RNS (e.g. superoxide radical and nitric oxide) occur at low/moderate concentrations and involve physiological roles in cellular responses to noxia, as for example in defence against infectious agents, in the function of a number of cellular signalling pathways, and the induction of a mitogenic response. Ironically, various ROS-mediated actions in fact protect cells against ROS-induced oxidative stress and re-establish or maintain "redox balance" termed also "redox homeostasis". The "two-faced" character of ROS is clearly substantiated. For example, a growing body of evidence shows that ROS within cells act as secondary messengers in intracellular signalling cascades which induce and maintain the oncogenic phenotype of cancer cells, however, ROS can also induce cellular senescence and apoptosis and can therefore function as anti-tumourigenic species. This review will describe the: (i) chemistry and biochemistry of ROS/RNS and sources of free radical generation; (ii) damage to DNA, to proteins, and to lipids by free radicals; (iii) role of antioxidants (e.g. glutathione) in the maintenance of cellular "redox homeostasis"; (iv) overview of ROS-induced signaling pathways; (v) role of ROS in redox regulation of normal physiological functions, as well as (vi) role of ROS in pathophysiological implications of altered redox regulation (human diseases and ageing). Attention is focussed on the ROS/RNS-linked pathogenesis of cancer, cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases (Alzheimer's disease and Parkinson's disease), rheumatoid arthritis, and ageing. Topics of current debate are also reviewed such as the question whether excessive formation of free radicals is a primary cause or a downstream consequence of tissue injury.
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PMID:Free radicals and antioxidants in normal physiological functions and human disease. 1697 5

In Parkinson's disease (PD), the selective depletion of dopamine neurons in the substantia nigra, particular those containing neuromelanin (NM), is the characteristic pathological feature. The role of NM in the cell death of dopamine neurons has been considered either to be neurotoxic or neuroprotective, but the precise mechanism has never been elucidated. In human brain, NM is synthesized by polymerization of dopamine and relating quinones, to which bind heavy metals including iron. The effects of NM prepared from human brain were examined using human dopaminergic SH-SY5Y cells. It was found that NM inhibits 26S proteasome activity through generation of reactive oxygen and nitrogen species from mitochondria. The mitochondrial dysfunction was also induced by oxidative stress mediated by iron released from NM. NM accumulated in dopamine neurons in ageing may determine the selective vulnerability of dopamine neurons in PD.
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PMID:The effect of neuromelanin on the proteasome activity in human dopaminergic SH-SY5Y cells. 1701 19

Increasing evidence suggests a critical role for oxidative and nitrosative stress in the pathogenesis of most important neurodegenerative disorders. Parkinson's disease (PD) is a neurodegenerative disease characterized by a severe depletion in number of dopaminergic cells of the substantia nigra (SN). Administration of L-DOPA (LD) is the more effective treatment for patients with PD. However, the vast majority of patients suffer LD-related complications, which represent the major problem in the clinical management of PD. In the present study, LD administration to rats resulted in a significant dose-dependent increase in Hsp70 synthesis which was specific for the SN. The amount of 70 kDa protein increased after 6 h treatment reaching the maximal induction after 24-48 h. Induction of Hsp70 in the SN was associated with a significant increase in constitutive Hsc70 and mitochondrial Hsp60 stress proteins, and with increased expression of mitochondrial complex I whereas no significant changes were found in the activity of complex IV. In the same experimental conditions, a significant decrease in reduced glutathione was observed, which was associated with an increased content of oxidized glutathione content as well as nitric oxide (NO) synthase activity, NO metabolites and nitrotyrosine immunoreactivity. Interestingly, Hsp70 induction, iNOS up-regulation and nitrotyrosine formation have been confirmed also in SN and striatum of rats treated with LD and carbidopa, this latter being an inhibitor of the peripheral DOPA decarboxylase. Our data are in favor of the importance of the heat shock signal pathway as a basic mechanism of defense against neurotoxicity elicited by free radical oxygen and nitrogen species produced in aging and neurodegenerative disorders.
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PMID:In vivo induction of heat shock proteins in the substantia nigra following L-DOPA administration is associated with increased activity of mitochondrial complex I and nitrosative stress in rats: regulation by glutathione redox state. 1724 Nov 15

Melatonin, a secretory product of the pineal gland, is involved in the regulation of circadian and seasonal rhythms, in oncostasis, and in inducing osteoblast differentiation. Furthermore, melatonin is a scavenger of a number of reactive oxygen and reactive nitrogen species both in vitro and in vivo. In this study, the antioxidant nature of melatonin was shown to prevent cultured neural cells from apoptosis induced by endocrine-disrupting chemical, maneb. The neurotoxicity of the fungicide, maneb (1 microg/mL), on the PC12 cells was elicited through apoptotic cell death, concomitant with aggregation of alpha-synuclein, a feature of Parkinson's disease. Activation of caspase-3/7 was associated with this process. A fluorescence rationing technique using a mitochondrial dye revealed that maneb altered the mitochondrial membrane potential of the neural cells. However, melatonin (1 nm) largely prevented the neural cells from the neural toxicant by inhibition of both caspase-3/7 activation and disruption of the mitochondrial transmembrane potential. Furthermore, aggregation of alpha-synuclein by maneb was also inhibited by melatonin. Thus, melatonin prevents maneb-induced neurodegeneration at a nighttime physiological blood concentration, most likely by inhibiting the aggregation of alpha-synuclein as well as preventing mitochondrial dysfunction in PC 12 cells.
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PMID:Melatonin inhibits maneb-induced aggregation of alpha-synuclein in rat pheochromocytoma cells. 1728 43

A variety of gene mutations can cause familial forms of Parkinson's disease (PD) or amyotrophic lateral sclerosis (ALS). Mutations in the synaptic protein alpha-synuclein (alpha-Syn) cause PD. Mutations in the antioxidant enzyme superoxide dismutase-1 (SOD1) cause ALS. The mechanisms of human mutant a-Syn and SOD1 toxicity to neurons are not known. Transgenic (tg) mice expressing human mutant alpha-Syn or SOD1 develop profound fatal neurologic disease characterized by progressive motor deficits, paralysis, and neurodegeneration. Ala-53-->Thr (A53T)-mutant alpha-Syn and Gly-93-->Ala (G93A)-mutant SOD1 tg mice develop prominent mitochondrial abnormalities. Interestingly, although nigral neurons in A53T mice are relatively preserved, spinal motor neurons (MNs) undergo profound degeneration. In A53T mice, mitochondria degenerate in neurons, and complex IV activity is reduced. Furthermore, mitochondria in neurons develop DNA breaks and have p53 targeted to the outer membrane. Nitrated a-Syn accumulates in degenerating MNs in A53T mice. mSOD1 mouse MNs accumulate mitochondria from the axon terminals and generate higher levels of reactive oxygen/nitrogen species than MNs in control mice. mSOD1 mouse MNs accumulate DNA single-strand breaks prior to double-strand breaks occurring in nuclear and mitochondrial DNA. Nitrated and aggregated cytochrome c oxidase subunit-I and nitrated SOD2 accumulate in mSOD1 mouse spinal cord. Mitochondria in mSOD1 mouse MNs accumulate NADPH diaphorase and inducible NOS (iNOS)-like immunoreactivity, and iNOS gene deletion significantly extends the lifespan of G93A-mSOD1 mice. Mitochondrial changes develop long before symptoms emerge. These experiments reveal that mitochondrial nitrative stress and perturbations in mitochondrial trafficking may be antecedents of neuronal cell death in animal models of PD and ALS.
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PMID:Transgenic mice with human mutant genes causing Parkinson's disease and amyotrophic lateral sclerosis provide common insight into mechanisms of motor neuron selective vulnerability to degeneration. 1759 75

There is growing evidence indicating that reactive nitrogen species (RNS) and reactive oxygen species (ROS) are a major contributor to the pathogenesis and progression of Parkinson's disease. Here we investigated whether edaravone (free radical scavenger), minocycline (inducible nitric oxide synthase, iNOS inhibitor), 7-nitroindazole (neuronal NOS, nNOS inhibitor), fluvastatin (endothelial NOS, eNOS activator) and pitavastatin (eNOS activator) can protect against MPTP neurotoxicity in mice under the same condition. The present study showed that 7-nitroindazole could protect dose-dependently against the striatal dopamine depletions in mice 5 days after MPTP treatment. In contrast, edaravone, minocycline, fluvastatin and pitavastatin did not show the neuroprotective effect on MPTP-induced striatal dopamine depletion. Our immunohistochemical study showed that TH (tyrosine hydroxylase) and DAT (dopamine transporter) immunoreactivity was decreased significantly in the striatum and substantia nigra 5 days after MPTP treatment. The administration of 7-nitroindazole showed a protective effect against the severe reductions in levels of TH and DAT immunoreactivity in the striatum and substantia nigra 5 days after MPTP treatment. Furthermore, our Western blot analyses study showed the remarkable loss of TH protein levels in the striatum 5 days after MPTP treatment. In contrast, 7-nitroindazole prevented a significant loss in TH protein levels in the striatum 5 days after MPTP treatment. On the other hand, GFAP (glial fibrillary acidic protein) immunoreactivity increased significantly in the striatum and substantia nigra, 5 days after MPTP treatment. 7-Nitroindazole ameliorated severe increases in number of GFAP immunoreactive astrocytes in the striatum and substantia nigra 5 days after MPTP treatment. Furthermore, our Western blot analyses study showed the increase of GFAP protein levels in the striatum 5 days after MPTP treatment. 7-Nitroindazole prevented a significant increase in the GFAP protein levels in the striatum 5 days after MPTP treatment. The present results indicate that 7-nitroindazole can protect dose-dependently against the striatal dopamine depletions in mice 5 days after MPTP treatment. In contrast, edaravone, minocycline, fluvastatin and pitavastatin did not show the neuroprotective effect on MPTP-induced striatal dopamine depletions. These findings demonstrate that the overexpression of nNOS may play a major role in the neurotoxic processes of MPTP, as compared to the production of ROS, the overexpression of iNOS and the modulation of eNOS. Thus, our findings provide strong evidence for neuroprotective properties of nNOS inhibitor in this animal model of Parkinson's disease.
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PMID:Role of reactive nitrogen and reactive oxygen species against MPTP neurotoxicity in mice. 1823 88

A growing body of evidence suggests oxidative stress involvement in neurodegenerative diseases; however, it remains to be determined whether oxidative stress is a cause, result, or epiphenomenon of the pathological processes. This review concerns the current issue, focusing on Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS). Several studies have indicated that oxidative stress initially occurs in the disease-specific, site-restricted sources such as amyloid-beta in the cerebral cortex of AD brain, alpha-synuclein in the brain stem of PD brain, and glutamate receptor-coupled Ca2+ channel in the motor system of ALS spinal cord. Subsequent events in the neurons common to these diseases are glutamate-induced neurotoxicity and increased cytosolic Ca2+ levels, resulting in activation of Ca2+ -dependent enzymes including NADPH oxidase, cytosolic phospholipase A2, xanthine oxidase, and neuronal nitric oxide synthase (NOS). These enzymes produce reactive oxygen and nitrogen species (ROS/RNS), which oxidatively modify nucleic acid, lipid, sugar, and protein, leading to nuclear damage, mitochondrial damage, proteasome inhibition, and endoplasmic reticulum (ER) stress. Mitochondrial damage results in both ROS leakage from the electron transport system and Ca2+ release. Nuclear damage induces p53 activation, and proteasome inhibition reduces p53 degradation. The resultant increased p53 levels in the nucleus induce Bax activation and Bcl-2 inhibition, followed by a release of cytochrome c into the cytosol that truncates procaspase-9. ER stress triggers activation of caspase-12 as well as caspase-9 via the tumor necrosis factor (TNF) receptor-associated factor-2 / apoptosis-signaling kinase-1 / c-Jun N-terminal kinase pathway. Oxidative stress also stimulates astrocytes and microglia to yield and secrete cytokines such as TNFa and FasL that cause not only neuronal caspase-8 activation but also glial inflammatory response through induction of nuclear factor-kappaB-mediated, proinflammatory gene products including cytokines, chemokines, growth factors, cell adhesion molecules, and ROS/RNS-producing enzymes. The activated caspases truncate procaspase-3 to exert classical apoptosis. Moreover, oxidative DNA damage leads to the release and nuclear truncation of mitochondrial apoptosis-inducing kinase, which triggers apoptosis-like programmed cell death via cyclophilin A. These observations could indicate crucial implications for oxidative stress in several steps of the pathomechanisms of neurodegenerative diseases.
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PMID:[The role for oxidative stress in neurodegenerative diseases]. 1830 64

Among age-related neurodegenerative diseases, Parkinson's disease (PD) represents the best example for which oxidative stress has been strongly implicated. The etiology of PD remains unknown, yet recent epidemiological studies have linked exposure to environmental agents, including pesticides, with an increased risk of developing the disease. As a result, the environmental hypothesis of PD has developed, which speculates that chemical agents in the environment are capable of producing selective dopaminergic cell death, thus contributing to disease development. The use of environmental agents such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, rotenone, paraquat, dieldrin, and maneb in toxicant-based models of PD has become increasingly popular and provided valuable insight into the neurodegenerative process. Understanding the unique and shared mechanisms by which these environmental agents act as selective dopaminergic toxicants is critical in identifying pathways involved in PD pathogenesis. In this review, we discuss the neurotoxic properties of these compounds with specific focus on the induction of oxidative stress. We highlight landmark studies along with recent advances that support the role of reactive oxygen and reactive nitrogen species from a variety of cellular sources as potent contributors to the neurotoxicity of these environmental agents. Finally, human risk and the implications of these studies in our understanding of PD-related neurodegeneration are discussed.
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PMID:Role of reactive oxygen species in the neurotoxicity of environmental agents implicated in Parkinson's disease. 1834 17


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