Inhibition of NADH oxidation by pyridine derivatives

Ramsay, Rona R.; McKeown, Kathleen A.; Johnson, Elizabeth A.; Booth, Raymond G.; Singer, Thomas P.

doi:10.1016/0006-291x(87)90689-9

Cited by 43 publications

(7 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…They cause a fall in mitochondrial membrane potential and opening of the mitochondrial transition pore that eventually leads to demise of the mitochondria and cell death. Previously, we have shown that 6‐OHDA is a potent inhibitor of mitochondrial complex I,68‐70 but significantly more potent than that reported with MPTP 71. The inhibition of complex I by 6‐OHDA has been attributed to 6‐OHDA itself rather than its oxidative products, where calcium significantly potentiates this effect.…”

Section: Discussionmentioning

confidence: 99%

Ironing Iron Out in Parkinson's Disease and Other Neurodegenerative Diseases with Iron Chelators: A Lesson from 6‐Hydroxydopamine and Iron Chelators, Desferal and VK‐28

Youdim

Stephenson

Shachar

2004

Annals of the New York Academy of Sciences

221

124

View full text Add to dashboard Cite

In Parkinson's disease (PD) and its neurotoxin-induced models, 6-hydroxydopamine (6-OHDA) and N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), significant accumulation of iron occurs in the substantia nigra pars compacta. The iron is thought to be in a labile pool, unbound to ferritin, and is thought to have a pivotal role to induce oxidative stress-dependent neurodegeneration of dopamine neurons via Fenton chemistry. The consequence of this is its interaction with H(2)O(2) to generate the most reactive radical oxygen species, the hydroxyl radical. This scenario is supported by studies in both human and neurotoxin-induced parkinsonism showing that disposition of H(2)O(2) is compromised via depletion of glutathione (GSH), the rate-limiting cofactor of glutathione peroxide, the major enzyme source to dispose H(2)O(2) as water in the brain. Further, radical scavengers have been shown to prevent the neurotoxic action of the above neurotoxins and depletion of GSH. However, our group was the first to demonstrate that the prototype iron chelator, desferal, is a potent neuroprotective agent in the 6-OHDA model. We have extended these studies and examined the neuroprotective effect of intracerebraventricular (ICV) pretreatment with the prototype iron chelator, desferal (1.3, 13, 134 mg), on ICV induced 6-OHDA (250 micro g) lesion of striatal dopamine neurons. Desferal alone at the doses studied did not affect striatal tyrosine hydroxylase (TH) activity or dopamine (DA) metabolism. All three pretreatment (30 min) doses of desferal prevented the fall in striatal and frontal cortex DA, dihydroxyphenylacetic acid, and homovalinic acid, as well as the left and right striatum TH activity and DA turnover resulting from 6-OHDA lesion of dopaminergic neurons. A concentration bell-shaped neuroprotective effect of desferal was observed in the striatum, with 13 micro g being the most effective. Neither desferal nor 6-OHDA affected striatal serotonin, 5-hydroxyindole acetic acid, or noradrenaline. Desferal also protected against 6-OHDA-induced deficit in locomotor activity, rearing, and exploratory behavior (sniffing) in a novel environment. Since the lowest neuroprotective dose (1.3 micro g) of desferal was 200 times less than 6-OHDA, its neuroprotective activity may not be attributed to interference with the neurotoxin activity, but rather iron chelation. These studies led us to develop novel brain-permeable iron chelators, the VK-28 series, with iron chelating and neuroprotective activity similar to desferal for ironing iron out from PD and other neurodegenerative diseases, such as Alzheimer's disease, Friedreich's ataxia, and Huntington's disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Ironing Iron Out in Parkinson's Disease and Other Neurodegenerative Diseases with Iron Chelators: A Lesson from 6‐Hydroxydopamine and Iron Chelators, Desferal and VK‐28

Youdim

Stephenson

Shachar

2004

Annals of the New York Academy of Sciences

221

124

View full text Add to dashboard Cite

show abstract

“…After this, the toxic substance is able to inhibit the oxidation of NADH-linked substrates by mitochondria (Nicklas et ai. 1985;Ramsay et al 1987). These results suggest that MPP+ metabolism of toxic action in vivo might be attributed to its inhibition of mitochondria1 functions and the subsequent ATP depletion (Mizuno et a/.…”

mentioning

confidence: 91%

Increased Striatal Lipid Peroxidation after Intracerebroventricular MPP+ Administration to Mice

Rojas

Rı́os

1993

Pharmacology & Toxicology

View full text Add to dashboard Cite

Mice received different doses intracerebroventricularly of MPP+ (1-methyl-4-phenylpyridinium ion), the active metabolite of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a drug which induces a Parkinson model in rodents. Two indexes of lipid peroxidation were monitored at different times after administration: 1) production of thiobarbituric acid-reactive substances and 2) formation of lipid fluorescence products. A regional-selective overproduction of thiobarbituric acid-reactive substances was observed in corpus striatum and midbrain, but not in frontal cortex, cerebellum nor hippocampus. Enhancement was 70% and 198% at 30 and 60 min. in striatum and 88% at 30 min. in midbrain, when compared with respective controls injected intracerebroventricularly with saline solution. MPP+ also induced lipid fluorescence products formation enhancement in corpus striatum. This increase was dose-dependent in the range of MPP+ doses which induced striatal dopamine depletion. Striatal LFP formation was found increased 24 hr after MPP+ administration (38% vs control), indicating long-lasting lipid peroxidation overproduction. These results suggest that lipid peroxidation might be involved in the neurotoxic effects of MPP+ in vivo.

show abstract

“…Early studies indicated that the rate of MPP+ uptake into mitochondria was apparently saturable, suggesting it to be carrier-mediated (Ramsay & Singer, 1986;Ramsay et al, 1987). However, subsequently it was found that charged and uncharged structural analogues of MPP+ were passively transported into the mitochondria in an energy-dependent manner (Hoppel et al, 1987), suggesting that uptake was not carrier-mediated.…”

Section: Introductionmentioning

confidence: 99%

Uptake and accumulation of 1-methyl-4-phenylpyridinium by rat liver mitochondria measured using an ion-selective electrode

Davey

Tipton

Murphy

1992

Biochemical Journal

View full text Add to dashboard Cite

The compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes selective destruction of nigrostriatal dopaminergic neurons in primates, giving rise to a condition resembling Parkinson's disease. The toxicity of MPTP is believed to be due to its metabolite 1-methyl-4-phenylpyridinium (MPP+). MPP+ is an inhibitor of mitochondrial respiration at the NADH-ubiquinone oxidoreductase site and this, together with its selective transport into dopaminergic nerve terminals, accounts for its neurotoxicity. In this paper an electrode selective for MPP+ was developed and used to measure the rate of uptake and the steady-state accumulation of MPP+ in rat liver mitochondria. The initial rates of MPP+ uptake were not saturable, confirming previous work that the transport of MPP+ is not carrier-mediated. The membrane potential of mitochondria respiring on succinate was decreased by MPP+ and the steady-state accumulation ratio of MPP+ did not come to equilibrium with the mitochondrial transmembrane potential gradient (delta psi). The effect of the cation exchanger tetraphenylboron (5 microM) was to increase the initial rate of MPP+ uptake by about 20-fold and the steady-state accumulation by about 2-fold. This suggests that there may be a mechanism of efflux of MPP+ from mitochondria which allows MPP+ to cycle across the membrane and thus decrease delta psi. These data indicate that MPP+ interacts with mitochondria independently of its inhibition of NADH-ubiquinone oxidoreductase, and these alternative interactions may be of relevance for its mechanism of neurotoxicity.

show abstract

Inhibition of NADH oxidation by pyridine derivatives

Cited by 43 publications

References 16 publications

Ironing Iron Out in Parkinson's Disease and Other Neurodegenerative Diseases with Iron Chelators: A Lesson from 6‐Hydroxydopamine and Iron Chelators, Desferal and VK‐28

Ironing Iron Out in Parkinson's Disease and Other Neurodegenerative Diseases with Iron Chelators: A Lesson from 6‐Hydroxydopamine and Iron Chelators, Desferal and VK‐28

Increased Striatal Lipid Peroxidation after Intracerebroventricular MPP+ Administration to Mice

Uptake and accumulation of 1-methyl-4-phenylpyridinium by rat liver mitochondria measured using an ion-selective electrode

Contact Info

Product

Resources

About