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)

Based on a number of lines of evidence, we have proposed recently that a very early step in the pathogenesis of idiopathic Parkinson's disease might be elevated translocation of L-cysteine into neuromelanin-pigmented dopaminergic cell bodies in the substantia nigra. In vitro studies suggest that such an influx of L-cysteine would divert the neuromelanin pathway by scavenging dopamine-o-quinone, the proximate autoxidation product of dopamine, to give 5-S-cysteinyldopamine, which is oxidized further to 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-1) and other cysteinyldopamines and dihydrobenzothiazines. In this study, it is demonstrated that DHBT-1 inhibits ADP-stimulated oxidation of malate and pyruvate (state 3 or complex I respiration) when incubated with intact rat brain mitochondria with an IC50 of approximatelly 0.80 mM. Incubation of DHBT-1 with freeze-thawed rat brain mitochondria in both the presence and absence of KCN and/or NADH causes an irreversible, time-dependent decrease of NADH-coenzyme Q1 reductase activity. Significantly lower concentrations of DHBT-1 are necessary to cause this effect when mitochondrial membranes are incubated in the absence of KCN and NADH. The irreversible inhibition of mitochondrial complex I caused by DHBT-1 under the latter conditions could be blocked only partially by glutathione, ascorbic acid, superoxide dismutase, or catalase. Together, these results suggest that DHBT-1 can cross the outer mitochondrial membrane and irreversibly inhibit complex I by a mechanism that is not primarily related to oxygen radical-mediated damage. Formation of DHBT-1 requires only dopamine, L-cysteine, and an oxidizing environment, conditions that may well exist in the cytoplasm of neuromelanin-pigmented dopaminergic neurons in the parkinsonian substantia nigra. The results of this study raise the possibility that DHBT-1 might be an endotoxin formed specifically in pigmented dopaminergic neurons that can contribute to irreversible damage to mitochondrial complex I and substantia nigra cell death in Parkinson's disease.
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PMID:Irreversible inhibition of mitochondrial complex I by 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxyli c acid (DHBT-1): a putative nigral endotoxin of relevance to Parkinson's disease. 932 82

We report Mn superoxide dismutase (SOD) protein and activity in a patient with familial autosomal recessive Lewy body-negative parkinsonism in comparison with patients with sporadic Parkinson's disease (PD) and controls. We recently proved linkage of this family with markers of chromosome 6 at 6q25.2-27, which included the Mn SOD gene. We used a novel polymorphic mutation at -9 position of the signal peptide of the Mn SOD precursor protein, which caused valine to alanine substitution. All the affected members of this family showed homozygosity for alanine, whereas nonaffected members, sporadic PD patients, and the control subjects studied showed either heterozygosity of alanine and valine or homozygosity of valine. The Mn SOD activity of this familial patient was the highest among the PD patients and the control subjects studied, and an abundant expression of Mn SOD was found in the substantia nigra. The molecular weight of Mn SOD protein by Western blotting of this patient was essentially similar to that of PD patients and the control subjects. High Mn SOD activity may constitute a genetic risk factor in this familial patient. The difference in the signal peptide sequence may affect the expression of Mn SOD within mitochondria; however, it is unlikely that loss of function type Mn SOD mutation is the cause of this familial parkinsonism. Mn SOD in sporadic PD patients was similar to that in controls.
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PMID:Mn SOD activity and protein in a patient with chromosome 6-linked autosomal recessive parkinsonism in comparison with Parkinson's disease and control. 937 4

Reactive oxygen species (ROS) have been implicated in a wide range of degenerative processes including amyotrophic lateral sclerosis, ischemic heart disease, Alzheimer disease, Parkinson disease and aging. ROS are generated by mitochondria as the toxic by-products of oxidative phosphorylation, their energy generating pathway. Genetic inactivation of the mitochondrial form of superoxide dismutase in mice results in dilated cardiomyopathy, hepatic lipid accumulation and early neonatal death. We report that treatment with the superoxide dismutase (SOD) mimetic Manganese 5, 10, 15, 20-tetrakis (4-benzoic acid) porphyrin (MnTBAP) rescues these Sod2tm1Cje(-/-) mutant mice from this systemic pathology and dramatically prolongs their survival. The animals instead develop a pronounced movement disorder progressing to total debilitation by three weeks of age. Neuropathologic evaluation reveals a striking spongiform degeneration of the cortex and specific brain stem nuclei associated with gliosis and intramyelinic vacuolization similar to that observed in cytotoxic edema and disorders associated with mitochondrial abnormalities such as Leighs disease and Canavans disease. We believe that due to the failure of MnTBAP to cross the blood brain barrier progressive neuropathology is caused by excessive mitochondrial production of ROS. Consequently, MnTBAP-treated Sod2tm1Cje(-/-) mice may provide an excellent model for examining the relationship between free radicals and neurodegenerative diseases and for screening new drugs to treat these disorders.
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PMID:A novel neurological phenotype in mice lacking mitochondrial manganese superoxide dismutase. 946 32

Oxidative stress may contribute to the neurodegenerative process in amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Motor cortex in PD is not affected and its inclusion in studies of free radical involvement in ALS pathogenesis could help elucidate whether oxidative stress is disease specific or a more widespread phenomenon present in the neurodegeneration. We have measured cytosolic and mitochondrial isoforms of superoxide dismutase (SOD), antioxidant enzymes involved in primary defence against free radical damage, in motor cortex of six patients with sporadic form of ALS (SALS), eight with PD and eight normal control subjects. We have found no difference in the activities of cytosolic and mitochondrial SOD between SALS and control motor cortex. Mitochondrial SOD activity in PD motor cortex was, however, significantly higher than in SALS and control motor cortex whereas activity of cytosolic SOD was lower than in two other groups although the differences were not statistically significant. Our findings indicate the presence of an altered antioxidant defence system in PD but not ALS upper motor neurons, suggesting that oxidative stress may be a widespread phenomenon in PD.
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PMID:Increased mitochondrial superoxide dismutase activity in Parkinson's disease but not amyotrophic lateral sclerosis motor cortex. 946 67

Paraquat has been implicated as an environmental toxin which may induce the syndrome of Parkinson's disease after exposure to this agent. However, the biochemical mechanism by which paraquat causes cell death and neurodegeneration has not been extensively studied. Paraquat was rapidly taken up by nerve terminals isolated from mouse cerebral cortices. It induced lipid peroxidation in a concentration dependent manner in the presence of NADPH and ferrous ion. The maximal stimulation effect was obtained at a paraquat concentration around 100 microM and the Km value for paraquat was 46.7 microM. The lipid peroxidation required microsomal enzymes. Antioxidants, such as superoxide dismutase, catalase and promethazine significantly inhibited paraquat-induced lipid peroxidation. Due to its structural similarity to the pyridinium compound MPP+ (N-methyl-4-phenyl pyridium ion), it may be taken up by dopamine neurons and cause lipid peroxidation and cell death resulting in the manifestation of Parkinsonian syndrome.
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PMID:Paraquat-induced free radical reaction in mouse brain microsomes. 948 66

beta-Phenylethylamine and its long acting derivatives, the amphetamines, are mixed-acting stimulants of the sympathetic system in the brain. They enhance the impulse propagation mediated release of catecholamines (catecholaminergic activity enhancer effect) and displace catecholamines from their stores (catecholamine releasing effect). (-)Deprenyl (selegiline), a close structural relative to (-)methamphetamine, is the first catecholaminergic activity enhancer substance in clinical use devoid of catecholamine releasing property, being therefore free of the 'cheese effect' and of the dependence capacity of the amphetamines. (-)Deprenyl is also a highly potent and selective, irreversible inhibitor of monoamine oxidase type B. (-)Deprenyl enhances superoxide dismutase and catalase activity in the striatum, protects the nigrostriatal dopaminergic neurons against selective neurotoxins (6-hydroxy-dopamine, MPTP, 4-N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) and prevents characteristic age-related morphological changes in the neurocytes of the substantia nigra. Maintenance of rats on (-)deprenyl during the postdevelopmental phase of their life slows the age-related decline of sexual and learning performances and prolongs life significantly. Patients with early, untreated Parkinson's disease maintained on (-)deprenyl need levodopa significantly later than their placebo-treated peers, and when on levodopa plus (-)deprenyl, they live significantly longer than patients on levodopa alone. In patients with moderately severe impairment from Alzheimer's disease, treatment with (-)deprenyl slows the progression of the disease. It may be supposed that a prophylactic low dose administration of a safe catecholaminergic activity enhancer substance during the postdevelopmental phase of life will slow the age-related decline of behavioral performances, delay natural death and decrease susceptibility to Parkinson's disease and Alzheimer's disease.
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PMID:(-)Deprenyl (selegiline), a catecholaminergic activity enhancer (CAE) substance acting in the brain. 949 33

Data on superoxide dismutase (SOD) activity in the cerebrospinal fluid (CSF) of patients suffering from dementia (n=32) as compared with a control group (n=58), a Parkinson disease (PD) patient group (n=12), and a group of individuals suffering from epilepsy (n=13) are presented. SOD activity was determined by electron spin resonance spectrometry using the spin trap method. No significant correlation was found between CSF SOD activity and age in the control group. In addition, CSF SOD activity was not gender dependent. One-way analysis of variance showed a highly significant between-groups effect for the CSF SOD activity and specific CSF SOD activity of the four major groups (p=0.0008). Post hoc comparison (Fisher PLSD test) revealed significant differences between the control group and the total dementia group (p < 0.001), between the dementia group and the epilepsy group (p < 0.01), and between the dementia group and the PD group (p < 0.05). The CSF of patients with PD or epilepsy showed a similar SOD activity as the CSF of control patients. In addition, CSF SOD activity levels were significantly lower in the total dementia group (p=0.002) and in the group with dementia of the Alzheimer type (DAT) (p=0.001) than in the dementia age-matched control group. No significant difference was found for CSF SOD activity levels between the control group and the non-DAT dementia group. This result corresponded with a reduction of CSF SOD activity in the total dementia group, DAT subgroup, and non-DAT subgroup of 37, 43, and 22%, respectively. No significant correlation between the Mini-Mental State Examination score and CSF SOD activity was found in DAT. The lowered CSF SOD activity in Alzheimer disease, as demonstrated here, may reflect impaired radical defense mechanisms and may have possible pathophysiological significance.
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PMID:Superoxide dismutase activity in cerebrospinal fluid of patients with dementia and some other neurological disorders. 953 7

Fermented papaya preparation is a natural health food that has been commercially sold in Japan for 2 years. It is made by yeast fermentation of Carica Papaya Linn. We examined the antioxidant action of the fermented papaya preparation on free radicals and lipid peroxidation. Free radicals have been related with aging and diseases, such as cancer, diabetes and especially in neurological disorders, for example, Parkinson's disease or Alzheimer's disease. A diet including variable antioxidant foods may therefore help to prevent these illnesses. The free radical scavenging activity of the fermented papaya preparation was examined using an electron spin resonance (ESR) spectrometer. Fermented papaya preparation (50 mg/ml) scavenged 80% of hydroxyl radicals (.OH) as spin adducts of spin trap, 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) (5.27 x 10(15)spins/ml) generated by Fenton reagents. The value of IC50 was 12.5 mg/ml. The oral administration of the fermented papaya preparation for 4 weeks decreased the elevated of lipid peroxide levels in the ipsilateral 30 min after injection of iron solution by iron into the left cortex of rats. The fermented papaya preparation also increased superoxide dismutase activity in the cortex and hippocampus of them. These results suggest that the fermented papaya preparation has antioxidant actions and that it may be prophylactic food against the age related and neurological diseases associated with free radicals.
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PMID:Free radical scavenging activity of fermented papaya preparation and its effect on lipid peroxide level and superoxide dismutase activity in iron-induced epileptic foci of rats. 963 26

Oxidative stress is implicated in several pathologies such as AIDS, Alzheimer's disease, and Parkinson's disease, as well as in normal aging. As a model system to study the response of cells to oxidative insults, glutamate toxicity on a mouse nerve cell line, HT-22, was examined. Glutamate exposure kills HT-22 via a nonreceptor-mediated oxidative pathway by blocking cystine uptake and causing depletion of intracellular glutathione (GSH), leading to the accumulation of reactive oxygen species and, ultimately, apoptotic cell death. Several HT-22 subclones that are 10-fold resistant to exogenous glutamate were isolated and the mechanisms involved in resistance characterized. The expression levels of neither heat shock proteins nor apoptosis-related proteins are changed in the resistant cells. In contrast, the antioxidant enzyme catalase, but not glutathione peroxidase nor superoxide dismutase, is more highly expressed in the resistant than in the parental cells. In addition, the resistant cells have enhanced rates of GSH regeneration due to higher activities of the GSH metabolic enzymes gamma-glutamylcysteine synthetase and GSH reductase, and GSH S-transferases activities are also elevated. As a consequence of these alterations, the glutamate resistant cells are also more resistant to organic hydroperoxides and anticancer drugs that affect these GSH enzymes. These results indicate that resistance to apoptotic oxidative stress may be acquired by coordinated changes in multiple antioxidant pathways.
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PMID:Cellular mechanisms of resistance to chronic oxidative stress. 964 Dec 55

Adenovirus is an efficient vector for neuronal gene therapy due to its ability to infect post-mitotic cells, its high efficacy of cell transduction and its low pathogenicity. Recombinant adenoviruses encoding for therapeutical agents can be delivered in vivo after direct intracerebral injection into specific brain areas. They can be transported in a retrograde manner from the injection site to the projection cell bodies offering promising applications for the specific targeting of selected neuronal populations not easily accessible by direct injection, such as the motor neurons in the spinal cord. Adenoviral vectors are also efficient tools for the ex vivo gene therapy, that is, the genetical modification of cells prior to their transplantation into the nervous system. Recently, the efficacy of the adenovirus as a gene vector system has been demonstrated in several models of neurodegenerative diseases including Parkinson's disease (PD) and motor neuron diseases. In rat models of PD, adenoviruses encoding for either tyrosine hydroxylase, superoxide dismutase or glial-derived neurotrophic factor improved the survival and the functional efficacy of dopaminergic cells. Similarly, the intramuscular injection of an adenovirus encoding for neurotrophin-3 had substantial therapeutic effects in a mutant mouse model of motor neuron degenerative disease. However, although adenoviruses are highly attractive for neuronal gene transfer, they can trigger a strong inflammatory reaction leading in particular to the destruction of infected cells. The recent development of new generations of adenoviral vectors could shed light on the nature of the immune reaction caused by adenoviral vectors in the brain. The use of these new vectors, combined with that of neurospecific and regulatable promoters, should improve adenovirus gene transfer into the central nervous system.
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PMID:Adenovirus in the brain: recent advances of gene therapy for neurodegenerative diseases. 965 83


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