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

Alcohol and aldehyde dehydrogenases (ADHs and ALDHs) may be of interest in the pathology of Parkinson's disease (PD) because of their role in protection against toxins and in retinoid metabolism, which is required for growth and development of the mesencephalic dopamine system. In the present study, the spatial and temporal expression patterns of Adh 1, Adh 3, Adh 4, and Aldh 1 mRNAs in embryonic C57BL/6 mice (E 9.5-E19.5) and Sprague-Dawley rats (E12.5-P0) have been investigated by using radioactive oligonucleotide in situ hybridization. High expression of Aldh 1 mRNA was found in the developing mesencephalic dopamine neurons of both mice and rats. Expression of Adh 1 and Adh 4 mRNAs was observed in adrenal cortex and olfactory epithelium in mice. Additionally, Adh 1 was expressed in epidermis, liver, conjunctival, and intestinal epithelium. In rat embryos, expression was less extensive, with Adh 1 mRNA being found in liver and intestines. Adh 3 expression was ubiquitous in both mouse and rat embryos, suggesting a housekeeping function of the gene. Consistent with previous studies in adult rats and mice, our data suggest that Adh 3 is the only ADH class present in rodent brain. Adh and Aldh gene activity in mouse and rat embryos indicate the possible involvement of the respective enzymes in retinoid metabolism and participation in defense against toxic insults, including those that may be involved in the pathogenesis of PD.
 ...
PMID:Tissue- and species-specific expression patterns of class I, III, and IV Adh and Aldh 1 mRNAs in rodent embryos. 1604 60

We explore the patterns of cell loss in the pedunculopontine tegmental nucleus (PpT), a major locomotor and muscle tone suppression centre of the brainstem, in two animal models of Parkinson disease, namely MPTP (methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated monkeys and 6-hydroxydopamine(6OHDA)-lesioned rats. Although there have been many studies documenting the loss of dopaminergic cells from the substantia nigra in these animal models, there has been little, if any, documentation of a loss of cells in the PpT. Results were obtained from macaque monkeys (Macaca fascicularis) and Sprague-Dawley rats. For the monkey series, animals were injected intramuscularly with MPTP (0.2 mg/kg) for 8 days consecutively and then allowed to survive for 21 days thereafter. Each monkey underwent behavioural assessment for parkinsonian symptoms. For the rat series, 6OHDA was injected into the midbrain using stereotactic coordinates. Rats were then allowed to survive for either 7, 14, 28, or 84 days thereafter. Monkey and rat brains were aldehyde-fixed and processed for routine tyrosine hydroxylase (TH; to label nigral dopaminergic cells) and nitric oxide synthase (NOs; to label PpT cholinergic cells) immunocytochemistry. In monkeys, the morphology, distribution and number of NOs(+) cells in the controls and MPTP-treated cases were very similar. In fact, in terms of number, there was only a 1% difference in the mean cell number between the controls and MPTP-treated cases. A comparable pattern was evident in 6OHDA-lesioned rats; there was no substantial difference in morphology, distribution and number of NOs(+) cells on the 6OHDA-lesioned cases when compared to the controls at each of the survival periods post-surgery. In summary, we show no loss of the large cholinergic/NOs(+) cells in the PpT in two animal models of Parkinson disease. This is in contrast to the heavy loss of these cells reported by previous findings in idiopathic Parkinson disease in patients.
 ...
PMID:Cell survival patterns in the pedunculopontine tegmental nucleus of methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys and 6OHDA-lesioned rats: evidence for differences to idiopathic Parkinson disease patients? 1623 36

Acetaldehyde, an inhibitor of mitochondrial function, has been widely used as a neurotoxin because it elicits a severe Parkinson's disease-like syndrome with elevation of the intracellular reactive oxygen species level and apoptosis. Rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, has been known to show various non-hypoglycemic effects, including anti-inflammatory, anti-atherogenic, and anti-apoptotic. In this study, we investigated the protective effects of rosiglitazone on acetaldehyde-induced apoptosis in human neuroblastoma SH-SY5Y cells and attempted to examine its mechanism. Acetaldehyde-induced apoptosis was moderately reversed by rosiglitazone treatment. Our results suggest that the protective effects of rosiglitazone on acetaldehyde-induced apoptosis may be ascribed to ability to induce the expression of anti-oxidant enzymes and to regulate Bcl-2 and Bax expression. These data indicate that rosiglitazone may provide a useful therapeutic strategy for the prevention of progressive neurodegenerative disease such as Parkinson's disease.
 ...
PMID:Rosiglitazone protects human neuroblastoma SH-SY5Y cells against acetaldehyde-induced cytotoxicity. 1636 Jan 19

Ubiquitin C-terminal hydrolases (UCHs) cleave Ub-X bonds (Ub is ubiquitin and X an alcohol, an amine, or a protein) through a thioester intermediate that is produced by nucleophilic attack of the Cys residue of a Cys-SH/His-Im catalytic diad. We are studying the mechanism of UCH-L1, a UCH that is implicated in Parkinson's disease, and now wish to report our initial findings. (i) Pre-steady-state kinetic studies for UCH-L1-catalyzed hydrolysis of Ub-AMC (AMC, 7-amido-4-methylcoumarin) indicate that k(cat) is rate-limited by acyl-enzyme formation. Thus, K(m) = K(s), the dissociation constant for the Michaelis complex, and k(cat) = k(2), the rate constant for acyl-enzyme formation. (ii) For K(assoc) (=K(s)(-)(1)), DeltaC(p) = -0.8 kcal mol(-)(1) deg(-)(1) and is consistent with coupling between substrate association and a conformational change of the enzyme. For k(2), DeltaS(++) = 0 and suggests that in the E-S, substrate and active site residues are precisely aligned for reaction. (iii) Solvent isotope effects are (D)K(assoc) = 0.5 and (D)k(2) = 0.9, suggesting that the substrate binds to a form of free enzyme in which the active site Cys exists as the thiol. In the resultant Michaelis complex, the diad has tautomerized to ion pair Cys-S(-)/His-ImH(+). Subsequent attack of thiolate produces the acyl-enzyme species. In contrast, isotope effects for association of UCH-L1 with transition-state analogue ubiquitin aldehyde suggest that an alternative mechanistic pathway can sometimes be available to UCH-L1 involving general base-catalyzed attack of Cys-SH by His-Im.
 ...
PMID:Mechanistic studies of ubiquitin C-terminal hydrolase L1. 1647 34

Acetaldehyde, an inhibitor of mitochondrial function, has been widely used as a neurotoxin because it elicits a severe Parkinson's disease-like syndrome with elevation of the intracellular reactive oxygen species (ROS) level and apoptosis. Adiponectin, secreted from adipose tissue, mediates systemic insulin sensitivity with liver and muscle as target organs. In this study, we investigated the protective effects of adiponectin on acetaldehyde-induced apoptosis in human neuroblastoma SH-SY5Y cells and attempted to examine its mechanism. Acetaldehyde-induced apoptosis was moderately reversed by adiponectin treatment. Our results suggest that the protective effects of adiponectin on acetaldehyde-induced apoptosis may be ascribed to ability to induce the expression of anti-oxidant enzymes and to regulate Bcl-2 and Bax expression. These data indicate that adiponectin may provide a useful therapeutic strategy for the prevention of progressive neurodegenerative disease such as Parkinson's disease.
 ...
PMID:Adiponectin protects human neuroblastoma SH-SY5Y cells against acetaldehyde-induced cytotoxicity. 1681 56

beta-Carbolines structurally related to the selective dopaminergic neurotoxin 1-methyl-4- phenylpyridinium (MPP(+)) may contribute to dopaminergic neurodegeneration in Parkinson's disease. The chloral-derived mammalian alkaloid derivative 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) is formed endogenously by a Pictet-Spengler condensation from the biogenic amine tryptamine (Ta) and the hypnotic aldehyde chloral (Clo). Here we examine the dopaminergic toxicity of TaClo and related compounds by testing their differential cytotoxicities in dopaminergic SH-SY5Y and non-dopaminergic murine Neuro2A neuroblastoma cell lines as well as in heterologous expression systems of the dopamine transporter (DAT) using both HEK-293 and Neuro2A cells. All TaClo derivatives showed significant cytotoxicity in all cell lines after 72 hours with the following rank order of toxic potency: 1-Tribromomethyl-1,2,3,4-tetrahydro-beta-carboline (TaBro) > TaClo > MPP(+) > 1,2,3,4-tetrahydro-beta-carboline (THbetaC) > 2[N]-methyl-TaClo > 2[N]-methyl-THbetaC. In contrast to MPP(+), there was no selectivity towards dopaminergic cells or cells ectopically expressing the DAT in vitro. Our results suggest that TaClo and related analogs are strong cytotoxins without selectivity towards dopaminergic cells.
 ...
PMID:Cytotoxicity of chloral-derived beta-carbolines is not specific towards neuronal nor dopaminergic cells. 1686 95

Recent evidence indicates a role for oxidative stress and resulting products, e.g. 4-hydroxy-2-nonenal (4HNE) in the pathogenesis of Parkinson's disease (PD). 4HNE is a known inhibitor of mitochondrial aldehyde dehydrogenase (ALDH2), an enzyme very important to the dopamine (DA) metabolic pathway. DA undergoes monoamine oxidase-catalyzed oxidative deamination to 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is metabolized primarily to 3,4-dihydroxyphenylacetic acid (DOPAC) via ALDH2. The biotransformation of DOPAL is critical as previous studies have demonstrated this DA-derived aldehyde to be a reactive electrophile and toxic to dopaminergic cells. Therefore, 4HNE produced via oxidative stress may inhibit ALDH2-mediated oxidation of the endogenous neurotoxin DOPAL. To test this hypothesis, ALDH2 in various model systems was treated with 4HNE and activity toward DOPAL measured. Incubation of human recombinant ALDH2 with 4HNE (1.5-30 microM) yielded inhibition of activity toward DOPAL. Furthermore, ALDH2 in rat brain mitochondrial lysate as well as isolated rat brain mitochondria was also sensitive to the lipid peroxidation product at low micromolar, as evident by a decrease in the rate of DOPAL to DOPAC conversion measured using HPLC. Taken together, these data indicate that 4HNE at low micromolar inhibits mitochondrial biotransformation of DOPAL to DOPAC, and generation of the lipid peroxidation product may represent a mechanism yielding aberrant levels of DOPAL, thus linking oxidative stress to the uncontrolled production of an endogenous neurotoxin relevant to PD.
 ...
PMID:Inhibition of the oxidative metabolism of 3,4-dihydroxyphenylacetaldehyde, a reactive intermediate of dopamine metabolism, by 4-hydroxy-2-nonenal. 1695 64

Among the several converging factors leading to Parkinson's disease, epidemiological studies indicate a correlation between Parkinson's disease (PD) with living in a rural area and/or exposure to agricultural pesticides. In this present study, we examined the potential of multiple agricultural pesticides for their ability to inhibit the function of whole, respiring rat brain mitochondria using the oxidation of the neurotoxic lipid-aldehyde trans-4-hydroxy-2-nonenal (HNE) as a biomarker for mitochondrial aldehyde dehydrogenase (ALDH) activity in situ. We chose an arbitrary cutoff concentration of 10 microM of each pesticide. Our data demonstrate that only four of the eighteen compounds tested inhibited oxidation of HNE to trans-4-hydroxy-2-nonenoic acid (HNEAcid). These compounds included rotenone, maneb, mancozeb, and benomyl. Surprisingly, maneb, mancozeb, and benomyl did not inhibit mitochondrial respiration but inhibited the activity of purified rat ALDH2 and rat ALDH5A, enzymes found in brain mitochondria that oxidize HNE and aldehydes derived from neurotransmitters. Our data demonstrate that mitochondrial ALDHs are sensitive targets of pesticide inactivation and that pesticides such as maneb and benomyl can decrease the detoxification of lipid peroxidation derived aldehydes such as HNE and, likely, aldehydes derived from neurotransmitters.
 ...
PMID:Inhibition of aldehyde detoxification in CNS mitochondria by fungicides. 1701 Apr 40

The underlying cause of Parkinson's disease is still enigma. Several mechanisms have been implicated in the etiopathogenesis of PD including oxidative damage, environmental toxins, genetic predisposition, and accelerated aging. Recent research suggests that salsolinol, a derivate of dopamine, is an important contributing factor. In the presence of acetaldehyde dopamine is converted into salsolinol, a neurotoxin involved in apoptosis of dopaminergic neurons. Increased production of acetaldehyde is associated with chronic polysystemic candidiasis (CPC). Chronically elevated levels of acetaldehyde in patients with CPC might participate in the formation of salsolinol and its metabolites in the brain contributing to the destruction of dopaminergic cells in substantia nigra. Clinical mental symptoms of PD often correspond with the mental manifestations of CPC. This hypothesis may constitute basis for further scientific and clinical research of PD etiopathogenesis (Fig. 1, Ref. 29).
 ...
PMID:Chronic polysystemic candidiasis as a possible contributor to onset of idiopathic Parkinson's disease. 1705 98

Parkinson's disease (PD) is a heterogeneous movement disorder characterized by progressive degeneration of dopamine neurons in substantia nigra. We have previously presented genetic evidence for the possible involvement of alcohol and aldehyde dehydrogenases (ADH; ALDH) by identifying genetic variants in ADH1C and ADH4 that associate with PD. The absence of the corresponding mRNA species in the brain led us to the hypothesis that one cause of PD could be defects in the defense systems against toxic aldehydes in the gastrointestinal tract. We investigated cellular expression of Adh1, Adh3, Adh4 and Aldh1 mRNA along the rodent GI tract. Using oligonucleotide in situ hybridization probes, we were able to resolve the specific distribution patterns of closely related members of the ADH family. In both mice and rats, Adh4 is transcribed in the epithelium of tongue, esophagus and stomach, whereas Adh1 was active from stomach to rectum in mice, and in duodenum, colon and rectum in rats. Adh1 and Adh4 mRNAs were present in the mouse gastric mucosa in nonoverlapping patterns, with Adh1 in the gastric glands and Adh4 in the gastric pits. Aldh1 was found in epithelial cells from tongue to jejunum in rats and from esophagus to colon in mice. Adh3 hybridization revealed low mRNA levels in all tissues investigated. The distribution and known physiological functions of the investigated ADHs and Aldh1 are compatible with a role in a defense system, protecting against alcohols, aldehydes and formaldehydes as well as being involved in retinoid metabolism.
 ...
PMID:High and complementary expression patterns of alcohol and aldehyde dehydrogenases in the gastrointestinal tract: implications for Parkinson's disease. 1725 71


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>