Oxidative stress during energy impairment in mesencephalic cultures is not a downstream consequence of a secondary excitotoxicity
Section snippets
Experimental procedures
Every effort was made to minimize animal suffering and to reduce the animals used for this study.
Energy impairment or glutamate exposure produces different alterations in intra- and extracellular glutathione
In order to demonstrate that oxidative stress is an early and potentially causal event in the sequelae of events associated with cell damage due to energy impairment or excitotoxicity rather than a downstream consequence, alterations indicative of oxidative stress should precede or occur concurrently with minimal exposure times necessary for toxicity. Our previous work showed that at least 6 h of exposure to 50 mM malonate was needed to cause dopamine cell loss, whereas longer times were required
Discussion
Defects in mitochondrial energy metabolism have been linked with Parkinson's disease.10., 33., 39., 45., 52. Whether reduced mitochondrial metabolism plays a primary, causative role in the disease is unknown. Regardless, reduced energy metabolism would likely impact on the surviving dopamine population during progression of the disease. Study of the mechanism(s) associated with dopaminergic cell loss due to impaired energy metabolism is, therefore, important in providing insight into their
Conclusions
Our findings indicate that the secondary excitotoxicity caused by impairment of energy metabolism with malonate does not contribute significantly to the oxidative stress that is observed. These findings may have relevance to the sequelae of cellular events that occur during neuronal loss in several neurodegenerative diseases in which mild impairments of mitochondrial metabolism have been described.
Acknowledgements
The authors wish to thank Hoechst Marion Roussel Research Institute (Cincinnati, OH) for their gift of MDL 102,832. This work was supported by U.S. Public Health Service grants NS 36157 and NS 17360.
References (63)
- et al.
Glutamate neurotoxicity is associated with nitric oxide-mediated mitochondrial dysfunction and glutathione depletion
Brain Res.
(1998) - et al.
The excitatory amino acid antagonist kynurenic acid administered after hypoxic-ischemia in neonatal rats offers neuroprotection
Neurosci. Lett.
(1988) - et al.
Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function
Neuron
(1995) - et al.
Chemical hypoxia increases cytosolic Ca2+ and oxygen free radical formation
Cell Calcium
(1995) - et al.
Increased excitotoxic vulnerability of cortical cultures with reduced levels of glutathione
Eur. J. Pharmac.
(1991) - et al.
Melatonin protects primary cultures of rat cortical neurones from NMDA excitotoxicity and hypoxia/reoxygenation
Brain Res.
(1997) - et al.
Inhibition of free radical production or free radical scavenging protects from the excitotoxic cell death mediated by glutamate in cultures of cerebellar granule neurons
Brain Res.
(1996) - et al.
Energy and glutamate dependency of 3-nitropropionic acid neurotoxicity in culture
Expl Neurol.
(1996) - et al.
Bioenergetics and glutamate excitotoxicity
Prog. Neurobiol.
(1996) Determination of glutathione and glutathione disulfide using glutathione reductase and 2-vinylpyridine
Analyt. Biochem.
(1980)
Ascorbate attenuates the systemic kainate-induced neurotoxicity in the rat
Brain Res.
Deficiencies in Complex I subunits of the respiratory chain in Parkinson's disease
Biochem. biophys. Res. Commun.
21-Aminosteroids attenuate excitotoxic neuronal injury in cortical cell cultures
Neuron
Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress
Neuron
Parkinson's disease: a disorder due to nigral glutathione deficiency?
Neurosci. Lett.
Characterization of the radical trapping activity of a novel series of cyclic nitrone spin traps
J. biol. Chem.
3-Nitropropionic acid is an indirect excitotoxin to cultured cerebellar granule neurons
Eur. J. Pharmac.
Neuroprotective effects of phenyl-t-butyl-nitrone in gerbil global brain ischemia and in cultured rat cerebellar neurons
Brain Res.
Glutamate neurotoxicity in rat cerebellar granule cells: a major role for xanthine oxidase in oxygen radical formation
J. Neurochem.
Synthetic combined superoxide dismutase/catalase mimetics are protective as a delayed treatment in a rat stroke model: a key role for reactive oxygen species in ischemic brain injury
J. Pharmac. exp. Ther.
An adenovirus encoding CuZnSOD protects cultured striatal neurones against glutamate toxicity
NeuroReport
Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid
J. Neurosci.
3-Nitropropionic acid neurotoxicity is attenuated in copper/zinc superoxide dismutase transgenic mice
J. Neurochem.
3-Nitropropionic acid induces apoptosis in cultured striatal and cortical neurons
NeuroReport
Electron transfer complexes I and IV of platelets are abnormal in Parkinson's disease but normal in Parkinson-plus syndromes
Brain
Age-dependent sensitivity of cultured peripheral sympathetic neurons to 1-methyl-4-phenylpyridinium: role of glutathione
J. Neurochem.
Superoxide production in rat hippocampal neurons: selective imaging with hydroethidine
J. Neurosci.
Apoptosis and necrosis: two distinct events induced respectively by mild and intense insults with N-methyl-d-aspartate or nitric oxide/superoxide in cortical cell cultures
Proc. natn. Acad. Sci. U.S.A.
The mitochondrial generation of hydrogen peroxide
Biochem. J.
Protection against oxidative damage to CNS by a-phenyl-tert-butyl nitrone (PBN) and other spin-trapping agents: a novel series of nonlipid free radical scavengers
J. molec. Neurosci.
The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death
A. Rev. Neurosci.
Cited by (23)
Rotigotine protects against glutamate toxicity in primary dopaminergic cell culture
2014, European Journal of PharmacologyCitation Excerpt :The toxic effects of glutamate were mediated via the NMDA receptor, as inhibition of the NMDA receptor by the non-competitive antagonist MK-801 completely abolished glutamate-induced toxicity (Fig. 1A). A complete or nearly complete protection of dopaminergic neurones in primary mesencephalic culture against glutamate toxicity by MK-801 has also been reported by others (Zeevalk et al., 2000; Izumi et al., 2009; Sawada et al., 1996c). In consequence of NMDA receptor activation we identified the influx of calcium resulting in a pronounced production of superoxide radicals as decisive for glutamate excitotoxicity.
The unsolved puzzle of neuropathogenesis in glutaric aciduria type I
2011, Molecular Genetics and MetabolismCitation Excerpt :Oxidative stress was shown to be induced by GA-I metabolites in several studies in rat striatal and chick embryonic neuronal cultures as well as astroglial cultures [33,88,108–111]. Inhibition of mitochondrial oxidative phosphorylation per se can enhance free radical production independently of Glu receptors [112,113] or via secondary excitotoxicity [114,115]. Overstimulation of NMDA receptors increases intracellular Ca2+ levels and catabolic enzyme activities that can trigger production of toxic oxygen and nitrogen free radicals [116–118].
Glutathione and Parkinson's disease: Is this the elephant in the room?
2008, Biomedicine and Pharmacotherapy