Glutathione Is Involved in the Granular Storage of Dopamine in Rat PC12 Pheochromocytoma Cells: Implications for the Pathogenesis of Parkinson’s Disease (original) (raw)
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Journal of Molecular Neuroscience, 2000
In order to examine the possible role of rat brain glutathione depletion by diethyl maleate (DEM) in the potentiation of 6-hydroxydopamine (6-OHDA) neurotoxicity, the relationships between both effects were evaluated using the circling behavior test (CBT), and determining striatal glutathione S-transferase (GST)-specific activity. There were significant differences between the two studied groups: 6-OHDA and DEM + 6-OHDA lesioned animals in striatal glutathione (GSH) concentration at the moment of the lesion with 6-OHDA and also at the end of the experiment (30 d after 6-OHDA lesion). The circling behavior test following the administration of amphetamine was qualitatively different between both groups of simpleand double-damaged animals. In accordance with our results, DEM injury makes the animals more susceptible to brain-oxidative damage by 6-OHDA, which can indicate that in the doubledamaged animal group, DEM could induce potentiation of the toxicity through striatal glutathione depletion.
Tetrahedron, 2001
ÐIn recent reports from this laboratory we have hypothesized that a key step underlying the degeneration of pigmented dopaminergic neurons in the substantia nigra pars compacta (SN c) in Parkinson's disease is an accelerated rate of oxidation of intraneuronal dopamine in the presence of l-cysteine (CySH) to form initially 5-S-cysteinyldopamine (5-S-CyS-DA). 5-S-CyS-DA, however, is more easily oxidized than dopamine in a reaction which leads to the dihydrobenzothiazine (DHBT) 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-1), a putative endogenously-formed metabolite that may be responsible for inhibition of mitochondrial complex I and a-ketoglutarate dehydrogenase, characteristic defects in the parkinsonian SN c. In this investigation it is demonstrated that glutathione (GSH) dramatically attenuates the oxidative transformation of 5-S-CyS-DA into DHBT-1 by two major pathways. In one pathway GSH displaces the cysteinyl residue from the o-quinone proximate oxidation product of 5-S-CyS-DA forming the corresponding glutathionyl conjugate that is attacked by GSH, to form 2,5-di-S-glutathionyldopamine, or by released CySH to give 2-Scysteinyl-5-S-glutathionyldopamine. The former is the precursor of 2,5,6-tris-S-glutathionyldopamine, a major reaction product. However, intramolecular cyclization of the o-quinone proximate product of 2-S-cysteinyl-5-S-glutathionyldopamine is the ®rst step in a pathway leading to glutathionyl conjugates of 8-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-5). The second pathway involves nucleophilic addition of GSH to the o-quinone proximate oxidation product of 5-S-CyS-DA forming 2-S-glutathionyl-5-S-cysteinyldopamine the precursor of a number of glutathionyl conjugates of DHBT-1. These results raise the possibility that strategies which elevate intraneuronal levels of GSH in dopaminergic SN c cells in Parkinson's disease patients may block formation of the putative mitochondrial toxin DHBT-1 and hence be neuroprotective.
Behavioural Brain Research, 2010
Early phases of Parkinson's disease (PD) are characterized by a mild reduction of dopamine (DA) in striatum and by emergence of psychiatric disturbances that precede overt motor symptoms. In order to characterize the neurochemical re-arrangements induced by such striatal impairment, we used a mouse model in which a low dose of 6-hydroxydopamine (6-OHDA) was bilaterally injected into the dorsal striatum. These mice showed a DA reduction of about 40% that remained stable up to 12 weeks after injection. This reduction was accompanied by changes in DA metabolite levels, such as HVA, transiently reduced at 4 weeks, and DOPAC, decreased at 12 weeks. No change in the 5-hydroxytryptamine (5-HT) levels was found but the 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratio was increased at 4 weeks. In addition, at the same time-point, the levels of 15-F 2t -IsoP, an index of oxidative stress, and of PGE 2 , a major product of cyclooxygenase-2, were decreased in different brain areas while BDNF levels were increased. These neurochemical changes were accompanied by altered behavioral responses concerning the emotional reactivity. Overall, the present findings suggest that a change of 5-HT metabolism and a modification of oxidative stress levels may play a role in the early PD degeneration phases.
Neurochemical Research, 2007
The unilateral and intrastriatal injection of 6-hydroxydopamine is commonly used to provide a partial lesion model of Parkinson’s disease in the investigation of the molecular mechanisms involved in its pathogenesis and to assess new neuroprotective treatments. Its capacity to induce neurodegeneration has been related to its ability to undergo autoxidation in the presence of oxygen and consequently to generate oxidative stress. The aim of the present study was to investigate the time course of brain oxidative damage induced by 6-hydroxydopamine (6 μg in 5 μl of sterile saline containing 0.2% ascorbic acid) injection in the right striatum of the rat. The results of this study show that the indices of both lipid peroxidation (TBARS) and protein oxidation (carbonyl and free thiol contents) increase simultaneously in the ipsilateral striatum and ventral midbrain, reaching a peak value at 48-h post-injection for both TBARS and protein carbonyl content, and at 24 h for protein free thiol content. A lower but significant increase was also observed in the contralateral side (striatum and ventral midbrain). The indices of oxidative stress returned to values close to those found in controls at 7-day post-injection. These data show that the oxidative stress is a possible triggering factor for the neurodegenerative process and the retrograde neurodegeneration observed after 1-week post-injection is a consequence of the cell damage caused during the first days post-injection. The optimal time to assess brain indices of oxidative stress in this model is 48-h post-injection.
Glutathione metabolism and Parkinson's disease
Free Radical Biology and Medicine, 2013
It has been established that oxidative stress, defined as the condition in which the sum of free radicals in a cell exceeds the antioxidant capacity of the cell, contributes to the pathogenesis of Parkinson disease. Glutathione is a ubiquitous thiol tripeptide that acts alone or in concert with enzymes within cells to reduce superoxide radicals, hydroxyl radicals, and peroxynitrites. In this review, we examine the synthesis, metabolism, and functional interactions of glutathione and discuss how these relate to the protection of dopaminergic neurons from oxidative damage and its therapeutic potential in Parkinson disease.
Glutathione‐related enzymes in brain in Parkinson's disease
Annals of Neurology, 1994
The activities of enzymes related to glutathione synthesis, degradation, and function were analyzed in various brain regions (cerebral cortex, caudate nucleus, putamen, globus pallidus, and substantia nigra) from patients dying with pathologically proven Parkinson's disease (PD) and multiple system atrophy (MSA), and from matched controls with no neurological disorder. The activity of the glutathione degradative enzyme, σ‐Glutamyltranspeptidase, was selectively elevated in substantia nigra (SN) in PD. In contrast, the activity of the synthetic enzyme, σ‐glutamylcysteine synthetase, was unaltered in SN and other brain areas in PD. Similarly, glutathione peroxidase and glutathione transferase activities were unaltered in SN or in other brain regions in PD. σ‐Glutamylcysteine synthetase, σ‐glutamyltranspeptidase, glutathione peroxidase, and glutathione transferase activities were normal in SN and most other brain areas in MSA. However, glutathione peroxidase activity was increased ...
NMR in Biomedicine
Degeneration of the dopaminergic neurons of the substantia nigra pars compacta in Parkinson's disease induces an abnormal activation of the glutamatergic neurotransmission system within the basal ganglia network and related structures. The aim of this study was to use proton MRS to show metabolic changes in the striatum of 6-hydroxydopamine-lesioned rats, a rodent animal model of Parkinson's disease. Animals were examined before and after extensive lesioning of the nigral dopaminergic neurons and after acute administration of L-3,4-dihydroxyphenylalanine. No significant alterations in glutamate concentrations, assessed by the MR signal dominated by glutamate with minor contributions from glutamine and gamma-aminobutyric acid, could be measured. The total choline/total creatine ratio was found to be reduced in the striatum of the ipsilateral hemisphere.