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)

Central nervous system has a low antioxidative capacity, which is formed mainly by ascorbic acid. Therefore the cerebral tissue is threatened by the increased formation of free radicals and their metabolites (ROS--reactive oxygen species). ROS are formed such as in reperfusion phase after ischemia and in catecholamine metabolism, in oxidative stress due to hyperglycaemia. Polyunsaturated fatty acids (PUFA) are peroxidased by ROS; proteins and DNK are damaged as well. Free radicals are involved in etiology and pathogenesis of many CNS diseases, such as neuritis, Alzheimer disease, Parkinson disease, Huntington disease, aging and atherosclerosis of the brain, epilepsy, etc. During the antioxidant therapy it is necessary to consider the types of ROS, their origin and their mode of action, whether to administer hydrophilic or lipophilic antioxidants, eventually chelate agents, etc. Hydrophylic antioxidants are acting very soon after the administration, whereas the lipophilic ones reach their target tissues with a great delay. Therefore it is better to apply them preferentially like a prevention, if possible. Enzymatic antioxidants (SOD, GSPHx and catalase and others) are usually acting only for a short time. The methods of estimation of free radicals attacks are discussed as well their possible pathophysiological effects.
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PMID:[Free radicals in the central nervous system]. 866 12

Neuronal damage in certain cellular populations in the brain has been linked to oxidative stress accompanied by an elevation in intracellular calcium. Many questions remain about how such oxidative stress occurs and how it affects calcium homeostasis. Glutathione (GSH) is a major regulator of cellular redox status in the brain, and lowered GSH levels have been associated with dopaminergic cell loss in Parkinson's disease (PD). We found that transfection of antisense oligomers directed against glutamylcysteine synthetase (GCS), the rate-limiting enzyme in GSH synthesis, into PC12 cells resulted in decreased GSH and increased levels of ROS. Decreased GSH levels also correlated with an increase in intracellular calcium levels. Data from this study suggest that dopaminergic neurons are very sensitive to decreases in the internal oxidant buffering capacity of the cell caused by reductions in GSH levels, and that alterations in this parameter can result in disruption of calcium homeostasis and cell death. These results may be of particular significance for therapeutic treatment of PD, as those dopaminergic neurons that are spared in this disorder appear to contain the calcium binding protein, calbindin.
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PMID:Decreased glutathione results in calcium-mediated cell death in PC12. 935 49

Although the aetiology of Parkinson's disease (PD) and related neurodegenerative disorders is still unknown, recent evidence from human and experimental animal models suggests that a misregulation of iron metabolism, iron-induced oxidative stress and free radical formation are major pathogenic factors. These factors trigger a cascade of deleterious events leading to neuronal death and the ensuing biochemical disturbances of clinical relevance. A review of the available data in PD provides the following evidence in support of this hypothesis: (i) an increase of iron in the brain, which in PD selectively involves neuromelanin in substantia nigra (SN) neurons; (ii) decreased availability of glutathione (GSH) and other antioxidant substances; (iii) increase of lipid peroxidation products and reactive oxygen (O2)species (ROS); and (iv) impaired mitochondrial electron transport mechanisms. Most of these changes appear to be closely related to interactions between iron and neuromelanin, which result in accumulation of iron and a continuous production of cytotoxic species leading to neuronal death. Some of these findings have been reproduced in animal models using 6-hydroxydopamine, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), iron loading and beta-carbolines, although none of them is an accurate model for PD in humans. Although it is not clear whether iron accumulation and oxidative stress are the initial events causing cell death or consequences of the disease process, therapeutic efforts aimed at preventing or at least delaying disease progression by reducing the overload of iron and generation of ROS may be beneficial in PD and related neurodegenerative disorders. Current pharmacotherapy of PD, in addition to symptomatic levodopa treatment, includes 'neuroprotective' strategies with dopamine agonists, monoamine oxidase-B inhibitors (MAO-B), glutamate antagonists, catechol O-methyltransferase inhibitors and other antioxidants or free radical scavengers. In the future, these agents could be used in combination with, or partly replaced by, iron chelators and lazaroids that prevent iron-induced generation of deleterious substances. Although experimental and preclinical data suggest the therapeutic potential of these drugs, their clinical applicability will be a major challenge for future research.
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PMID:The role of iron in neurodegeneration: prospects for pharmacotherapy of Parkinson's disease. 1008 65

Altered energy metabolism is characteristic of many neurodegenerative disorders. Reductions in the key mitochondrial enzyme complex, the alpha-ketoglutarate dehydrogenase complex (KGDHC), occur in a number of neurodegenerative disorders including Alzheimer's Disease (AD). The reductions in KGDHC activity may be responsible for the decreases in brain metabolism, which occur in these disorders. KGDHC can be inactivated by several mechanisms, including the actions of free radicals (Reactive Oxygen Species, ROS). Other studies have associated specific forms of one of the genes encoding KGDHC (namely the DLST gene) with AD, Parkinson's disease, as well as other neurodegenerative diseases. Reductions in KGDHC activity can be plausibly linked to several aspects of brain dysfunction and neuropathology in a number of neurodegenerative diseases. Further studies are needed to assess mechanisms underlying the sensitivity of KGDHC to oxidative stress and the relation of KGDHC deficiency to selective vulnerability in neurodegenerative diseases.
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PMID:The alpha-ketoglutarate dehydrogenase complex in neurodegeneration. 1067 73

Parkinson's disease (PD) is characterized by pathological changes which include degeneration of dopaminergic neurons in the substantia nigra pars compacta coupled with intracytoplasmic inclusions known as Lewy bodies. Neurodegeneration and Lewy bodies can also be found in the locus coeruleus, nucleus basalis, hypothalamus, cerebral cortex, cranial nerve motor nuclei, and central and peripheral components of the autonomic nervous system. PD progression is associated with the development of dementia, autonomic dysfunction, and postural instability, which do not respond well to conventional therapy. Therapeutic efforts aimed at preventing or at least delaying PD progression by reducing the overload of iron and generation of ROS, correcting the zinc deficiency may be of great benefit. Current pharmacotherapy of PD, in addition to symptomatic L-dopa treatment, includes the neuroprotective strategies with dopamine agonists, monoamine oxidase-B inhibitors (MAO-B), glutamate antagonists, catechol O-methyltransferase (COMT) inhibitors and other antioxidants or free radical scavengers. Depression, anxiety disorder and stress are all associated with PD and it is therefore necessary to include treatment regimens for these ailments in addition to the traditional pharmacotherapy for the symptoms of PD, as well as the neuroprotective measures noted above, in order to ensure the greatest possible benefit to PD patients.
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PMID:Importance of treatment of depression in assuring the most efficacious management of Parkinson's disease. 1090 82

Recent etiological study in twins (Tanner et al. 1999) strongly suggests that environmental factors play an important role in typical, non-familial Parkinson's disease (PD), beginning after age 50. Epidemiological risk factor analyses of typical PD cases have identified several neurotoxicants, including MPP(+) (the active metabolite of MPTP), paraquat, dieldrin, manganese and salsolinol. Here, we tested the hypothesis that these neurotoxic agents might induce cell death in our nigral dopaminergic cell line, SN4741 (Son et al. 1999) through a common molecular mechanism. Our initial experiments revealed that treatment with both MPP(+) and the other PD-related neurotoxicants induced apoptotic cell death in SN4741 cells, following initial increases of H(2)O(2)-related ROS activity and subsequent activation of JNK1/2 MAP kinases. Moreover, we have demonstrated that during dopaminergic cell death cascades, MPP(+), the neurotoxicants and an oxidant, H(2)O(2) equally induce the ROS-dependent events. Remarkably, the oxidant treatment alone induced similar sequential molecular events: ROS increase, activation of JNK MAP kinases, activation of the PITSLRE kinase, p110, by both Caspase-1 and Caspase-3-like activities and apoptotic cell death. Pharmacological intervention using the combination of the antioxidant Trolox and a pan-caspase inhibitor Boc-(Asp)-fmk (BAF) exerted significant neuroprotection against ROS-induced dopaminergic cell death. Finally, the high throughput cDNA microarray screening using the current model identified downstream response genes, such as heme oxygenase-1, a constituent of Lewy bodies, that can be the useful biomarkers to monitor the pathological conditions of dopaminergic neurons under neurotoxic insult.
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PMID:Dopaminergic cell death induced by MPP(+), oxidant and specific neurotoxicants shares the common molecular mechanism. 1118 20

Oxidative stress, reactive oxygen (ROS), and nitrogen (RNS) species have been known to be involved in a multitude of neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Both ROS and RNS have very short half-lives, thereby making their identification very difficult as a specific cause of neurodegeneration. Recently, we have developed a high performance liquid chromatography/electrochemical detection (HPLC/EC) method to identify 3-nitrotyrosine (3-NT), an in vitro and in vivo biomarker of peroxynitrite production, in cell cultures and brain to evaluate if an agent-driven neurotoxicity is produced by the generation of peroxynitrite. We show that a single or multiple injections of methamphetamine (METH) produced a significant increase in the formation of 3-NT in the striatum. This formation of 3-NT correlated with the striatal dopamine depletion caused by METH administration. We also show that PC12 cells treated with METH has significantly increased formation of 3-NT and dopamine depletion. Furthermore, we report that pretreatment with antioxidants such as selenium and melatonin can completely protect against the formation of 3-NT and depletion of striatal dopamine. We also report that pretreatment with peroxynitrite decomposition catalysts such as 5, 10,15,20-tetrakis(N-methyl-4'-pyridyl)porphyrinato iron III (FeTMPyP) and 5, 10, 15, 20-tetrakis (2,4,6-trimethyl-3,5-sulfonatophenyl) porphinato iron III (FETPPS) significantly protect against METH-induced 3-NT formation and striatal dopamine depletion. We used two different approaches, pharmacological manipulation and transgenic animal models, in order to further investigate the role of peroxynitrite. We show that a selective neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole (7-NI), significantly protect against the formation of 3-NT as well as striatal dopamine depletion. Similar results were observed with nNOS knockout and copper zinc superoxide dismutase (CuZnSOD)-overexpressed transgenic mice models. Finally, using the protein data bank crystal structure of tyrosine hydroxylase, we postulate the possible nitration of specific tyrosine moiety in the enzyme that can be responsible for dopaminergic neurotoxicity. Together, these data clearly support the hypothesis that the reactive nitrogen species, peroxynitrite, plays a major role in METH-induced dopaminergic neurotoxicity and that selective antioxidants and peroxynitrite decomposition catalysts can protect against METH-induced neurotoxicity. These antioxidants and decomposition catalysts may have therapeutic potential in the treatment of psychostimulant addictions.
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PMID:Methamphetamine-induced dopaminergic neurotoxicity: role of peroxynitrite and neuroprotective role of antioxidants and peroxynitrite decomposition catalysts. 1146 92

Oxidative stress phenomena have been related with the onset of neurodegenerative diseases. Particularly in Alzheimer Disease (AD), oxygen reactive species (ROS) and its derivatives can be found in brain samples of postmortem AD patients. However, the mechanisms by which oxygen reactive species can alter neuronal function are still not elucidated. There is a growing amount of evidence pointing to a role for mitochondrial damage as the source of free radicals involved in oxidative stress. Among the species that participate in the production of oxygen reactive radicals, transition metals are one of the most important. Several reports have implicated the involvement of redox-active metals with the onset of different neurodegenerative diseases such as Alzheimer's Disease (AD), Progressive Supranuclear Palsy (PSP), Amyotrophic Lateral Sclerosis (ALS) and Parkinson's Disease (PD). On the other hand, our previous studies have indicated that A beta-induced deregulation of the protein kinase Cdk5 associated with tau protein hyperphosphorylation constitute a critical pathway toward neurodegeneration. In the current paper we have shown that iron induces an imbalance in the function of Cdk5/p25 system of hippocampal neurons, resulting in a marked decrease in tau phosphorylation at the typical Alzheimer's epitopes. The loss of phosphorylated tau epitopes correlated with an increase in 4-hydroxy-nonenal (HNE) adducts revealing damage by oxidative stress. This effects on tau phosphorylation patterns seems to be a consequence of a decrease in the Cdk5/p25 complex activity that appears to result from a depletion of the activator p25, a mechanism in which calcium transients could be implicated.
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PMID:Iron-induced oxidative stress modify tau phosphorylation patterns in hippocampal cell cultures. 1257 81

Manganese (Mn) is an essential metal that, at excessive levels in the brain, produces extrapyramidal symptoms similar to those in patients with Parkinson's disease (PD). In the present study, Mn toxicity was characterized in a human neuroblastoma (SK-N-SH) cell line and in a mouse catecholaminergic (CATH.a) cell line. Mn was demonstrated to be more toxic in the catecholamine-producing CATH.a cells (EC50 = 60 microM) than in non-catecholaminergic SK-N-SH cells (EC50 = 200 microM). To test the hypothesis that the sensitivity of CATH.a cells to Mn is associated with their dopamine (DA) content, DA concentrations were suppressed in these cells by pretreatment with alpha-methyl-para-tyrosine (AMPT). Treatment for 24 h with 100 microM AMPT decreased intracellular DA, but offered no significant protection from Mn exposure (EC50 = 60 microM). Additional studies were carried out to assess if Mn toxicity was dependent on glutathione (GSH) levels. CATH.a cells were significantly protected by the addition of 5mM GSH (Mn EC50 = 200 microM) and 10mM N-acetyl cysteine (NAC) (Mn EC50 = 300 microM), therefore, indirectly identifying intracellular ROS formation as a mechanism for Mn neurotoxicity. Finally, apoptotic markers of Mn-induced cell death were investigated. DNA fragmentation, caspase-3 activation, and apoptosis-related gene expression were studied in CATH.a cells. No internucleosomal fragmentation or caspase activation was evident, even in the presence of "supraphysiological" Mn concentrations. cDNA hydridization array analysis with two differing Mn concentrations and time points, identified no noteworthy mRNA inductions of genes associated with programmed cell death. In conclusion, DA content was not responsible for the enhanced sensitivity of CATH.a cells to Mn toxicity, but oxidative stress was implicated as a probable mechanism of cytotoxicity.
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PMID:Manganese-induced cytotoxicity in dopamine-producing cells. 1518 9

6-Hydroxydopamine (6-OHDA) is widely used to produce an animal model of Parkinson's disease by selectively destroying the catecholaminergic nerve system of the substantia nigra. In our previous studies we noted that dopaminergic neuroblastoma cells (SH-SY5Y) die mostly via apoptosis after exposure to 6-OHDA (< or = 100 microM) but African green monkey fibroblast (CV1-P) cells do not succumb, although in both cell lines there were increased intracellular p53 levels. This study was designed to further investigate the mechanisms underlying the p53 elevation. To test how 6-OHDA penetrates into fibroblast cells and affects p53 levels, we investigated the presence of the dopamine transporter (DAT) in CV1-P cells. We showed by western hybridization that CV1-P cells contain the DAT. The apparent entry of 6-OHDA into fibroblasts was decreased by the DAT inhibitor, 1-(2-bis-(4-fluorophenyl)methoxy)ethyl)-4-(3-phenyl-propyl)piperazine (GBR 12909). Pre-treatment with GBR 12909 decreased the elevation of intracellular ROS to the control level and thus prevented the increase of p53 levels in 6-OHDA-treated CV1-P cells. Moreover, an increase of Bcl-2, an antiapoptotic protein, was detected after 6-OHDA treatment, supporting our previous results where no increase in caspase-3 activity was detected. We suggest that Bcl-2 may block the activation of the caspase cascade and protect CV1-P cells from apoptosis.
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PMID:The roles of dopamine transporter and Bcl-2 protein in the protection of CV1-P cells from 6-OHDA-induced toxicity. 1547 85


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