Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.3 (complex I)
 8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Current concepts of the cause of Parkinson's disease (PD) suggest a role for both genetic and environmental influences. Common to a variety of potential causes of nigral cell degeneration in PD is the involvement of oxidative stress. Postmortem analysis shows increased levels of iron, decreased complex I activity, and a decrease in reduced glutathione (GSH) levels. The decrease in GSH levels may be a particularly important component of the cascade of events leading to cell death because it occurs in the presymptomatic stage of PD and may directly induce nigral cell degeneration or render neurons susceptible to the actions of toxins. There is evidence suggesting that oxidative stress might originate in glial cells rather than in neurons, and alterations in glial function may be an important contributor to the pathologic process that occurs in PD. Oxidative damage occurs in the brain in PD, as shown by increased lipid peroxidation and DNA damage in the substantia nigra. Increased protein oxidation is also apparent, but this occurs in many areas of the brain and raises the specter of a more widespread pathologic process occurring in PD to which the substantia nigra is particularly vulnerable. The inability of the substantia nigra to handle damaged or mutant (eg, alpha-synuclein) proteins may lead to their aggregation and deposition and to the formation of Lewy bodies. Indeed, Lewy bodies stain for both alpha-synuclein and nitrated proteins. Current evidence enables us to hypothesize that a failure to process structurally modified proteins in regions of the brain exhibiting oxidative stress is a cause of both familial and sporadic PD.
 ...
PMID:Understanding cell death in Parkinson's disease. 974 77

The mechanisms that lead to mitochondrial damage under oxidative stress conditions were examined in synaptosomes treated with ascorbate/iron. A loss of membrane integrity, evaluated by electron microscopy and by LDH leakage, was observed in peroxidized synaptosomes and it was prevented by pre-incubation with vitamin E (150 microM) and idebenone (50 microM). ATP levels decreased, in synaptosomes exposed to ascorbate/iron, as compared to controls. NADH-ubiquinone oxidoreductase (Cx I) and cytochrome c oxidase (Cx IV) activities were unchanged after ascorbate/iron treatment, whereas succinate-ubiquinone oxidoreductase (Cx II), ubiquinol cytochrome c reductase (Cx III) and ATP-synthase (Cx V) activities were reduced by 55%, 40%, and 55%, respectively. The decrease of complex II and ATP-synthase activities was prevented by reduced glutathione (GSH), whereas the other antioxidants tested (vitamin E and idebenone) were ineffective. However, vitamin E, idebenone and GSH prevented the reduction of complex III activity observed in synaptosomes treated with ascorbate/iron. GSH protective effect suggests that the oxidation of protein SH-groups is involved in the inhibition of complexes II, III and V activity, whereas vitamin E and idebenone protection suggests that membrane lipid peroxidation is also involved in the reduction of complex III activity. These results may indicate that the inhibition of the mitochondrial respiratory chain enzymatic complexes, that are differentially affected by oxidative stress, can be recovered by specific antioxidants.
 ...
PMID:Mitochondrial function is differentially affected upon oxidative stress. 989 Jun 35

We have examined the effects of a variety of classical and atypical neuroleptic drugs on mitochondrial NADH ubiquinone oxido-reductase (complex I) activity. Sagittal slices of mouse brain incubated in vitro with haloperidol (10 nM) showed time- and concentration-dependent inhibition of complex I. Similar concentrations of the pyridinium metabolite of haloperidol (HPP+) failed to inhibit complex I activity in this model; indeed, comparable inhibition was obtained only at a 10000-fold higher concentration of HPP+ (100 microM). Treatment of brain slices with haloperidol resulted in a loss of glutathione (GSH), while pretreatment of slices with GSH and alpha-lipoic acid abolished haloperidol-induced loss of complex I activity. Incubation of mitochondria from haloperidol treated brain slices with the thiol reductant, dithiothreitol, completely regenerated complex I activity demonstrating thiol oxidation as a feasible mechanism of inhibition. In a comparison of different neuroleptic drugs, haloperidol was the most potent inhibitor of complex I, followed by chlorpromazine, fluphenazine and risperidone while the atypical neuroleptic, clozapine (100 microM) did not inhibit complex I activity in mouse brain slices. The present studies support the view that classical neuroleptics such as haloperidol inhibit mitochondrial complex I through oxidative modification of the enzyme complex.
 ...
PMID:Inhibition of mitochondrial complex I by haloperidol: the role of thiol oxidation. 1022 60

In this investigation, microdialysis has been used to study the effects of 1-methyl-4-phenylpyridinium (MPP+), an inhibitor of mitochondrial complex I and alpha-ketoglutarate dehydrogenase and the active metabolite of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), on extracellular concentrations of glutathione (GSH) and cysteine (CySH) in the rat striatum and substantia nigra (SN). During perfusion of a neurotoxic concentration of MPP+ (2.5 mM) into the rat striatum or SN, extracellular concentrations of GSH and CySH remain at basal levels (both approximately 2 microM). However, when the perfusion is discontinued, a massive but transient release of GSH occurs, peaking at 5,000% of basal levels in the striatum and 2,000% of basal levels in the SN. The release of GSH is followed by a slightly delayed and smaller elevation of extracellular concentrations of CySH that can be blocked by the gamma-glutamyl transpeptidase (gamma-GT) inhibitor acivicin. Low-molecular-weight iron and extracellular hydroxyl radical (OH*) have been implicated as participants in the mechanism underlying the dopaminergic neurotoxicity of MPTP/MPP+. During perfusion of Fe2+ (OH*) into the rat striatum and SN, extracellular levels of GSH also remain at basal levels. When perfusions of Fe2+ are discontinued, a massive transient release of GSH occurs followed by a delayed, small, but progressive elevation of extracellular CySH level that again can be blocked by acivicin. Previous investigators have noted that extracellular concentrations of the excitatory/excitotoxic amino acid glutamate increase dramatically when perfusions of neurotoxic concentrations of MPP+ are discontinued. This observation and the fact that MPTP/MPP+ causes the loss of nigrostriatal GSH without corresponding increases of glutathione disulfide (GSSG) and the results of the present investigation suggest that the release and gamma-GT/dipeptidase-mediated hydrolysis of GSH to glutamate, glycine, and CySH may be important factors involved with the degeneration of dopamine neurons. It is interesting that a very early event in the pathogenesis of Parkinson's disease is a massive loss of GSH in the SN pars compacta that is not accompanied by corresponding increases of GSSG levels. Based on the results of this and prior investigations, a new hypothesis is proposed that might contribute to an understanding of the mechanisms that underlie the degeneration of dopamine neurons evoked by MPTP/MPP+, other agents that impair neuronal energy metabolism, and Parkinson's disease.
 ...
PMID:Inhibitors of mitochondrial respiration, iron (II), and hydroxyl radical evoke release and extracellular hydrolysis of glutathione in rat striatum and substantia nigra: potential implications to Parkinson's disease. 1050 Dec 16

Altered glial function in the substantia nigra in Parkinson's disease may lead to the release of toxic substances that cause dopaminergic cell death or increase neuronal vulnerability to neurotoxins. To investigate this concept, we examined the effects of subjecting astrocytes to lipopolysaccharide (LPS)-induced activation alone or combined with L-buthionine-[S,R]-sulfoximine-induced glutathione depletion or inhibition of complex I activity by 1-methyl-4-phenylpyridinium (MPP+) on the viability of primary ventral mesencephalic neurones or susceptibility to MPP+ and 6-hydroxydopamine (6-OHDA) in co-cultures. LPS-activated astrocytes caused neuronal death in a time-dependent manner, but glutathione-depleted or complex I-inhibited astrocytes had no effect on neuronal viability. The neurotoxicity of LPS-activated astrocytes was inhibited by the inducible nitric oxide synthase inhibitor aminoguanidine, by the nitric oxide scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, and by reduced glutathione (GSH). MPP+-induced neuronal death was greater in ventral mesencephalic cultures previously cultured with LPS-activated, glutathione-depleted, or complex I-inhibited astrocytes compared with co-cultures containing normal astrocytes. The increased neuronal susceptibility to MPP+ caused by LPS-activated or complex I-inhibited astrocytes and glutathione-depleted astrocytes was inhibited by the NMDA/glutamate antagonist MK-801 and by GSH, respectively. Neuronal death caused by 6-OHDA was increased in ventral mesencephalic cultures previously cultured with LPS-activated and glutathione-depleted, but not complex I-inhibited astrocytes, compared with co-cultures containing normal astrocytes. Treatment of co-cultures with GSH prevented the increased neuronal susceptibility to 6-OHDA. These findings suggest that glial dysfunction may cause neuronal death or render neurones susceptible to toxic insults via a mechanism involving the release of free radicals and glutamate. Such a mechanism may play a role in the development or progression of nigrostriatal degeneration in Parkinson's disease.
 ...
PMID:Altered glial function causes neuronal death and increases neuronal susceptibility to 1-methyl-4-phenylpyridinium- and 6-hydroxydopamine-induced toxicity in astrocytic/ventral mesencephalic co-cultures. 1058 7

We investigated the effect of the selective dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP+) on glutathione redox status and the generation of reactive oxygen intermediates (ROI) in rat pheochromocytoma PC 12 cells in vitro. Treatment with MPP+ (250 microM) led to a 63% increase of reduced glutathione (GSH) after 24 h, while a 10-fold higher concentration of MPP+ (2.5 mM) depleted cellular GSH to 12.5% of control levels within that time. Similarly, the complex I-inhibitor rotenone induced a time-dependent loss of GSH at 1 and 10 microM, whereas treatment with lower concentrations of rotenone (0.1, 0.01 microM) increased cellular GSH. Both MPP+ and rotenone increased cellular levels of oxidised glutathione (GSSG) and the higher concentrations of both compounds led to an elevated ratio of oxidised glutathione (GSSG) vs total glutathione (GSH + GSSG) indicating a shift in cellular redox balance. MPP+ or rotenone did not induce the generation of ROI or significant elevation of intracellular levels of thiobabituric acid reactive substances (TBARS) for up to 48 h. Our data suggest that MPP+ has differential effects on glutathione homeostasis depending on the degree of complex I-inhibition and that inhibition of complex I is not sufficient to generate ROI in this paradigm.
 ...
PMID:Effect of 1-methyl-4-phenylpyridinium on glutathione in rat pheochromocytoma PC 12 cells. 1076 85

Glycosphingolipids, including gangliosides, are emerging as signaling intermediates of extracellular stimuli. Because mitochondria play a key role in the orchestration of death signals, we assessed the interaction of GD3 ganglioside (GD3) with mitochondria and the subsequent cascade of events that culminate in cell death. In vitro studies with isolated mitochondria from rat liver demonstrate that GD3 elicited a burst of peroxide production within 15-30 min, which preceded the opening of the mitochondrial permeability transition, followed by cytochrome c (cyt c) release. These effects were mimicked by lactosylceramide and N-acetyl-sphingosine but not by sphinganine or sphingosine and were prevented by cyclosporin A and butylated hydroxytoluene (BHT). Reconstitution of mitochondria pre-exposed to GD3 with cytosol from rat liver in a cell-free system resulted in the proteolytic processing of procaspase 3 and subsequent caspase 3 activation. Intact hepatocytes or U937 cells selectively depleted of glutathione in mitochondria by 3-hydroxyl-4-pentenoate (HP) with the sparing of cytosol reduced glutathione (GSH) were sensitized to GD3, manifested as an apoptotic death. Inhibition of caspase 3 prevented the apoptotic phenotype of HP-treated cells caused by GD3 without affecting cell survival; in contrast, BHT fully protected HP-treated cells to GD3 treatment. Treatment of cells with tumor necrosis factor increased the level of GD3, whereas blockers of mitochondrial respiration at complex I and II protected sensitized cells to GD3 treatment. Thus, the effect of GD3 as a lipid death effector is determined by its interaction with mitochondria leading to oxidant-dependent caspase activation. Mitochondrial glutathione plays a key role in controlling cell survival through modulation of the oxidative stress induced by glycosphingolipids.
 ...
PMID:Direct interaction of GD3 ganglioside with mitochondria generates reactive oxygen species followed by mitochondrial permeability transition, cytochrome c release, and caspase activation. 1078 38

Altered glial cell function occurring in substantia nigra in Parkinson' disease may lead to the release of cytokines and impairment of neurotrophic factor production, which in turn, may cause dopaminergic apoptosis. To evaluate this concept, primary cultures of rat brain astrocytes were activated with lipopolysaccharide (LPS), depleted of glutathione with L-buthionine-[S,R]-sulfoximine or subjected to complex I inhibition with 1-methyl-4-phenylpyridinium. The effects on tumour necrosis factor-alpha (TNF-alpha) release, dopamine-stimulated glial cell line derived neurotrophic factor (GDNF) and brain derived neurotrophic factor (BDNF) release were determined. LPS activation or inhibition complex I activity, but not glutathione depletion, stimulated TNF-alpha release. Glutathione depletion or complex I inhibition, but not LPS-induced activation, impaired dopamine-stimulated GDNF release. None of these treatments altered BDNF release. Thus, altered glial function leading to TNF-alpha-mediated or GDNF withdrawal-induced dopaminergic apoptosis may contribute to nigral degeneration in Parkinson's disease.
 ...
PMID:Dysfunction of rat forebrain astrocytes in culture alters cytokine and neurotrophic factor release. 1078 8

Oxidative stress appears to play an important role in degeneration of dopaminergic neurons of the substantia nigra (SN) associated with Parkinson's disease (PD). The SN of early PD patients have dramatically decreased levels of the thiol tripeptide glutathione (GSH). GSH plays multiple roles in the nervous system both as an antioxidant and a redox modulator. We have generated dopaminergic PC12 cell lines in which levels of GSH can be inducibly down-regulated via doxycycline induction of antisense messages against both the heavy and light subunits of gamma-glutamyl-cysteine synthetase, the rate-limiting enzyme in glutathione synthesis. Down-regulation of glutamyl-cysteine synthetase results in reduction in mitochondrial GSH levels, increased oxidative stress, and decreased mitochondrial function. Interestingly, decreases in mitochondrial activities in GSH-depleted PC12 cells appears to be because of a selective inhibition of complex I activity as a result of thiol oxidation. These results suggest that the early observed GSH losses in the SN may be directly responsible for the noted decreases in complex I activity and the subsequent mitochondrial dysfunction, which ultimately leads to dopaminergic cell death associated with PD.
 ...
PMID:Glutathione depletion in PC12 results in selective inhibition of mitochondrial complex I activity. Implications for Parkinson's disease. 1084 69

Although it is considered that L-Glutamine (L-Gln) supplementation improves gut morphology and survival in animal models such as radiation and drug-induced enterocolitis, the mechanisms underlying are far from being established. Recently, Gln has been reported to give protection against stress in in vitro intestinal epithelial cell lines through the induction of heat shock proteins (HSPs). This study is designed to examine whether L-Gln may induce cytoprotective molecules such as heme oxygenase-1/HSP32 (HO-1) and reduced glutathione (GSH) in in vivo intestinal tissues, and to clarify whether these molecules may play a role in warm ischemia and reperfusion (I/R) injury. We measured the releases of serotonin and tumor necrosis factor-alpha (TNF-alpha), and graft survival as viability assays following reperfusion of warm ischemically injured intestinal grafts. The substantial expression of HO-1 after L-Gln administration was observed in villous epithelial cells, crypts and muscular layers, and peaked at 6 h, while that of the control group pretreated with lactated Ringer (LR) solution was observed throughout tissues to be slightly similar to those of fresh untreated tissues. Tissue GSH contents slightly increased 24 h after administration and were less reduced through the periods of I/R than those of the LR group. Releases of serotonin and TNF-alpha in L-Gln group were attenuated during the brief periods of warm ischemia, compared with those in the LR group. A significant graft survival rate was also observed between both groups (6/6 of L-Gln group vs. 1/6 of LR group; p < 0.05). In conclusion, the protective effects of L-Gln in small intestines against warm I/R injury were considered to be in part mediated by up-regulation of molecules such as HO-1 and GSH via cellular antioxidant activity. Thus, L-Gln pretreatment may represent an innovative approach to the prevention of complex I/R injury.
 ...
PMID:[L-glutamine-induced heme oxygenase-1 protects small intestine from warm ischemia and reperfusion injury in the rat]. 1123 9


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