Inhibition of neuronal nitric oxide synthase prevents MPTP–induced parkinsonism in baboons

Hantraye, Philippe; Brouillet, Emmanuel; Ferrante, Robert J.; Palfi, Stéphane; Dolan, Raymond J.; Matthews, Russell T.; Beal, M. Flint

doi:10.1038/nm0996-1017

Cited by 400 publications

(218 citation statements)

References 28 publications

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“…A similar sequence of events has recently been proposed (Cleeter et al 1994) to explain the link between mitochondrial impairment and long-term neurological disorders, e.g. Huntingdon's disease (Jenkins et al 1993) and Parkinson's disease (Hantraye et al 1996).…”

Section: (B) Neonatal Hypoxia-ischaemiamentioning

confidence: 54%

Measurement of cytochrome oxidase and mitochondrial energetics by near–infrared spectroscopy

Cooper

Springett

1997

Phil. Trans. R. Soc. Lond. B

139

111

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SUMMARYCytochrome oxidase is the terminal electron acceptor of the mitochondrial respiratory chain. It is responsible for the vast majority of oxygen consumption in the body and essential for the efficient generation of cellular ATP. The enzyme contains four redox active metal centres ; one of these, the binuclear Cu A centre, has a strong absorbance in the near-infrared that enables it to be detectable in i o by near-infrared spectroscopy. However, the fact that the concentration of this centre is less than 10 % of that of haemoglobin means that its detection is not a trivial matter.Unlike the case with deoxyhaemoglobin and oxyhaemoglobin, concentration changes of the total cytochrome oxidase protein occur very slowly (over days) and are therefore not easily detectable by nearinfrared spectroscopy. However, the copper centre rapidly accepts and donates an electron, and can thus change its redox state quickly ; this redox change is detectable by near-infrared spectroscopy. Many factors can affect the Cu A redox state in i o , but the most significant is likely to be the molecular oxygen concentration (at low oxygen tensions, electrons build up on Cu A as reduction of oxygen by the enzyme starts to limit the steady-state rate of electron transfer).The factors underlying haemoglobin oxygenation, deoxygenation and blood volume changes are, in general, well understood by the clinicians and physiologists who perform near-infrared spectroscopy measurements. In contrast, the factors that control the steady-state redox level of Cu A in cytochrome oxidase are still a matter of active debate, even amongst biochemists studying the isolated enzyme and mitochondria. Coupled with the difficulties of accurate in i o measurements it is perhaps not surprising that the field of cytochrome oxidase near-infrared spectroscopy has a somewhat chequered past. Too often papers have been written with insufficient information to enable the measurements to be repeated and few attempts have been made to test the algorithms in i o.In recent years a number of research groups and commercial spectrometer manufacturers have made a concerted attempt to not only say how they are attempting to measure cytochrome oxidase by nearinfrared spectroscopy but also to demonstrate that they are really doing so. We applaud these attempts, which in general fall into three areas : first, modelling of data can be performed to determine what problems are likely to derail cytochrome oxidase detection algorithms (Matcher et al. 1995) ; secondly haemoglobin concentration changes can be made by haemodilution (using saline or artificial blood substitutes) in animals (Tamura 1993) or patients (Skov & Greisen 1994) ; and thirdly, the cytochrome oxidase redox state can be fixed by the use of mitochondrial inhibitors and then attempts made to cause spurious cytochrome changes by dramatically varying haemoglobin oxygenation, haemoglobin concentration and light scattering (Cooper et al. 1997).We have previously written reviews covering the difficulties of measuring the cyt...

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Section: (B) Neonatal Hypoxia-ischaemiamentioning

confidence: 54%

Measurement of cytochrome oxidase and mitochondrial energetics by near–infrared spectroscopy

Cooper

Springett

1997

Phil. Trans. R. Soc. Lond. B

139

111

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“…If one assumes that a concentration gradient is operative from its local of synthesis (the mitochondria) and the extracellular fluid, its concentration in brain mitochondria might be much higher than that in CSF; (ii) an increased turnover of dopamine (synthesis and metabolism) is observed in the early stages of Parkinson's disease (Bernheimer et al, 1973;Hornykiewicz and Kish, 1996;Strange, 1992). Such a compensatory mechanism, increasing the cytoplasmic availability of dopamine, may boost DOPAC concentration due to activated monoamine oxidase activity (Hastings and Zigmond, 1997;Cubells et al, 1994;Sulzer et al, 1995); (iii) an increased NO formation in Parkinson's disease has been widely suggested (Gerlach et al, 1999;Hantraye et al, 1996;Itzhak and Ali, 1996;Schulz et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the inhibition of nNOS (neuronal nitric oxide synthase) prevents Parkinsonism in animal models of the disease (Schulz et al, 1995;Hantraye et al, 1996;Przedborski et al, 1996;Dehmer et al, 2000;Klivenyi et al, 2000;Watanabe et al, 2004Watanabe et al, , 2008.…”

Section: Introductionmentioning

confidence: 99%

3,4-Dihydroxyphenylacetic acid (DOPAC) modulates the toxicity induced by nitric oxide in PC-12 cells via mitochondrial dysfunctioning

2008

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“…Neurotoxic effects of NO are also mediated by peroxynitrite (ONOO À ), a reaction product of NO and superoxide anion (O 2 the progression of disease pathology in animal models of PD, AD, and ALS, suggesting that excess generation of NO plays a pivotal role in the pathogenesis of several neurodegenerative diseases. [34][35][36] Recent studies further pointed out the potential connection between ROS/RNS and mitochondrial dysfunction in neurodegenerative diseases, especially in PD. 37,38 Pesticide and other environmental toxins that inhibit mitochondrial complex I result in oxidative and nitrosative stress, and consequent aberrant protein accumulation.…”

mentioning

confidence: 99%

S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding

Nakamura

Lipton

2007

Cell Death Differ

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Although activation of glutamate receptors is essential for normal brain function, excessive activity leads to a form of neurotoxicity known as excitotoxicity. Key mediators of excitotoxic damage include overactivation of N-methyl-D-aspartate (NMDA) receptors, resulting in excessive Ca 2 þ influx with production of free radicals and other injurious pathways. Overproduction of free radical nitric oxide (NO) contributes to acute and chronic neurodegenerative disorders. NO can react with cysteine thiol groups to form S-nitrosothiols and thus change protein function. S-nitrosylation can result in neuroprotective or neurodestructive consequences depending on the protein involved. Many neurodegenerative diseases manifest conformational changes in proteins that result in misfolding and aggregation. Our recent studies have linked nitrosative stress to protein misfolding and neuronal cell death. Molecular chaperones -such as protein-disulfide isomerase, glucose-regulated protein 78, and heat-shock proteins -can provide neuroprotection by facilitating proper protein folding. Here, we review the effect of S-nitrosylation on protein function under excitotoxic conditions, and present evidence that NO contributes to degenerative conditions by S-nitrosylating-specific chaperones that would otherwise prevent accumulation of misfolded proteins and neuronal cell death. In contrast, we also review therapeutics that can abrogate excitotoxic damage by preventing excessive NMDA receptor activity, in part via S-nitrosylation of this receptor to curtail excessive activity.

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Inhibition of neuronal nitric oxide synthase prevents MPTP–induced parkinsonism in baboons

Cited by 400 publications

References 28 publications

Measurement of cytochrome oxidase and mitochondrial energetics by near–infrared spectroscopy

Measurement of cytochrome oxidase and mitochondrial energetics by near–infrared spectroscopy

3,4-Dihydroxyphenylacetic acid (DOPAC) modulates the toxicity induced by nitric oxide in PC-12 cells via mitochondrial dysfunctioning

S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding

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