Oxidative stress and antioxidant therapy in Parkinson's disease

Ebadi, Manuchair; Srinivasan, Shashi K.; Baxi, Mayur D.

doi:10.1016/0301-0082(95)00029-1

Cited by 305 publications

(166 citation statements)

References 182 publications

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“…for midbrain dopaminergic neurons and other neuronal and nonneuronal cell populations (Dumont and Beal, 2011;Ebadi et al, 1996;Fariss and Zhang, 2003;Koppula et al, 2012aKoppula et al, , 2012bMayo et al, 2005;Sharma and Nehru, 2013). However, the results of human clinical trials are inconsistent in slowing down disease progression, but there is still hope that improved antioxidant mimetics that better target ROS production pathways might prove beneficial.…”

Section: Discussionmentioning

confidence: 99%

Nanomicellar formulation of coenzyme Q10 (Ubisol-Q10) effectively blocks ongoing neurodegeneration in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model: potential use as an adjuvant treatment in Parkinson's disease

Sikorska

Lanthier

Miller

et al. 2014

Neurobiology of Aging

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Although the support for the use of antioxidants, such as coenzyme Q 10 (CoQ 10 ), to treat Parkinson's disease (PD) comes from the extensive scientific evidence, the results of conducted thus far clinical trials are inconclusive. It is assumed that the efficacy of CoQ 10 is hindered by insolubility, poor bioavailability, and lack of brain penetration. We have developed a nanomicellar formulation of CoQ 10 (Ubisol-Q 10 ) with improved properties, including the brain penetration, and tested its effectiveness in mouse MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) model with the objectives to assess its potential use as an adjuvant therapy for PD. We used a subchronic MPTP model (5-daily MPTP injections), characterized by 50% loss of dopamine neurons over a period of 28 days. Ubisol-Q 10 was delivered in drinking water. Prophylactic application of Ubisol-Q 10 , started 2 weeks before the MPTP exposure, significantly offset the neurotoxicity (approximately 50% neurons died in MPTP group vs. 17% in MPTP+ Ubisol-Q 10 group by day 28). Therapeutic application of Ubisol-Q 10 , given after the last MPTP injection, was equally effective. At the time of intervention on day 5 nearly 25% of dopamine neurons were already lost, but the treatment saved the remaining 25% of cells, which otherwise would have died by day 28. This was confirmed by cell counts, analyses of striatal dopamine levels, and improved animals' motor skill on a beam walk test. Similar levels of neuroprotection were obtained with 3 different Ubisol-Q 10 concentrations tested, that is, 30 mg, 6 mg, or 3 mg CoQ 10 /kg body weight/day, showing clearly that high doses of CoQ 10 were not required to deliver these effects. Furthermore, the Ubisol-Q 10 treatments brought about a robust astrocytic activation in the brain parenchyma, indicating that astroglia played an active role in this neuroprotection. Thus, we have shown for the first time that Ubisol-Q 10 was capable of halting the neurodegeneration already in progress;

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Section: Discussionmentioning

confidence: 99%

Nanomicellar formulation of coenzyme Q10 (Ubisol-Q10) effectively blocks ongoing neurodegeneration in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model: potential use as an adjuvant treatment in Parkinson's disease

Sikorska

Lanthier

Miller

et al. 2014

Neurobiology of Aging

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“…Excitatory amino acid receptor blockers such as dizocilpine attenuate MPP ϩ -induced neurotoxicity. Amfonelic acid and Mazindol, preventing the uptake of MPTP into dopaminergic neurons, and selegiline, preventing the formation of MPP ϩ , prevent the neurotoxic effects of MPTP (see also Ebadi et al, 1996;Ebadi and Hiramatsu, 2000;Naoi and Maruyama, 2001;Szende et al, 2001). placebo (P ϭ 0.03). Disability was significantly less in the selegiline group than in the placebo group up to 12 months.…”

Section: Selegiline Possesses Neurotrophic-like Action and Rescues Axmentioning

confidence: 99%

“…Today, MPTP-induced toxicity represents one of the most interesting models for investigating the pathogenesis of the parkinsonian syndrome. However, its mechanism of action is still not fully understood (see Jankovic, 1994;Ebadi et al, 1996;Montastruc et al, 1996;Ebadi and Hiramatsu, 2000;Knoll, 2000;Nicotra and Parvez, 2000).…”

mentioning

confidence: 99%

Neuroprotective actions of selegiline

Ebadi

Sharma

Shaik

et al. 2002

J of Neuroscience Research

121

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Selegiline, a selective inhibitor of monoamine oxidase-B (MAO-B), was one of the first adjunct therapies in clinical neurology. A retrospective analysis of data from patients with Parkinson's disease found a significant increase in survival in those treated with selegiline plus L-dopa compared with L-dopa alone. The mechanism of action of selegiline is complex and cannot be explained solely by its MAO-B inhibitory action. Pretreatment with selegiline can protect neurons against a variety of neurotoxins, such as 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), 6-hydroxydopamine, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), methyl-␤-acetoxyethyl-2-chloroethylamine (AF64A), and 5,6-dihydroxyserotonin, which damage dopaminergic, adrenergic, cholinergic, and sertoninergic neurons, respectively. Selegiline produces an amphetamine-like effect, enhances the release of dopamine, and blocks the reuptake of dopamine. It stimulates gene expression of L-aromatic amino acid decarboxylase, increases striatal phenylethylamine levels, and activates dopamine receptors. Selegiline reduces the production of oxidative radicals, up-regulates superoxide dismutase and catalase, and suppresses nonenzymatic and iron-catalyzed autooxidation of dopamine. Selegiline compensates for loss of target-derived trophic support, delays apoptosis in serum-deprived cells, and blocks apoptosis-related fall in the mitochondrial membrane potential. Most of the aforementioned properties occur independently of selegiline's efficacy to inhibit MAO-B. © 2002 Wiley-Liss, Inc.Selegiline (deprenyl; Jumex), a noncompetitive monoamine oxidase-B (MAO-B) inhibitor, has continued to hold a fascination for clinicians and researchers since it was first synthesized as a "psychic energizer." The "neuroprotective effects" of selegiline became evident when it was found that it blocked the parkinsonism-inducing effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; see Langston and Tanner, 2000).MPTP as a neurotoxin has attracted the attention of many investigators owing to its capacity in humans and nonhuman primates to induce neuropathologic abnormalities (rigidity, resting tremor, akinesia, etc.) similar to those observed in patients with idiopathic Parkinson's disease (PD). As in PD also after administration of MPTP, the observed symptoms are caused by depletion of dopamine in the neostriatum following selective degeneration of the dopaminergic neurons of the substantia nigra pars compacta (SNpc).MPTP's capacity to induce PD was discovered accidentally when several drug addicts in California developed numerous symptoms of PD after self-administration of a "synthetic heroin" containing MPTP as a contaminant byproduct. Numerous investigations have since been carried out in which MPTP was administered in vivo to primates and rodents as well as in vitro using cell cultures. Today, MPTP-induced toxicity represents one of the most interesting models for investigating the pathogenesis of the parkinsonian syndrome. However, its mechanism of action is stil...

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“…However, the limited bioavailability, inefficient permeability, and other untoward effects associated with the use of the individual exogenous antioxidative compounds raised questions on their effectiveness in protecting against PD (Ebadi et al, 1996;Ratnam et al, 2006). In this regard, another strategy to protect against the oxidative and electrophilic processes underlying PD may be through coordinated induction of endogenous antioxidants and phase 2 enzymes in neuronal cells by chemical inducers, such as 3H-1,2-dithiole-3-thione (D3T), the most potent member of dithiolethiones for induction of phase 2 enzymes.…”

Section: Introductionmentioning

confidence: 99%

Potent induction of total cellular GSH and NQO1 as well as mitochondrial GSH by 3H-1,2-dithiole-3-thione in SH-SY5Y neuroblastoma cells and primary human neurons: Protection against neurocytotoxicity elicited by dopamine, 6-hydroxydopamine, 4-hydroxy-2-nonenal, or hydrogen peroxide

et al. 2008

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Evidence suggests oxidative and electrophilic stress as a major factor contributing to the neuronal cell death in neurodegenerative disorders, especially Parkinson's disease. Consistent with this concept, administration of exogenous antioxidants has been shown to be protective against oxidative/ electrophilic neurodegeneration. However, whether induction of endogenous antioxidants and phase 2 enzymes by the unique chemoprotectant, 3H-1,2-dithiole-3-thione (D3T) in neuronal cells also affords protection against oxidative and electrophilic neurocytotoxicity has not been carefully investigated. In this study, we showed that incubation of SH-SY5Y neuroblastoma cells or primary human neurons with micromolar concentrations (10-100 μM) of D3T for 24 h resulted in significant increases in the levels of reduced glutathione (GSH) and NAD(P)H:quinone oxidoreductase 1 (NQO1), two crucial cellular defenses against oxidative and electrophilic stress. D3T treatment also caused increases in mRNA expression of γ-glutamylcysteine ligase catalytic subunit and NQO1 in SH-SY5Y cells. In addition, D3T treatment of the neuronal cells also resulted in a marked elevation of GSH content in the mitochondrial compartment. To determine the protective effects of the D3T-induced cellular defenses on neurotoxicant-elicited cell injury, SH-SY5Y cells were pretreated with D3T for 24 h and then exposed to dopamine, 6-hydroxydopamine (6-OHDA), 4-hydroxy-2-nonenal (HNE), or H 2 O 2 , agents that are known to be involved in neuron degeneration. We observed that D3T-pretreatment of SH-SY5Y cells led to significant protection against the cytotoxicity elicited by the above neurotoxicants. Similar neurocytoprotective effects of D3T-pretreatment were also observed in primary human neurons exposed to 6-OHDA or HNE. Taken together, this study demonstrates that D3T potently induces neuronal cellular GSH and NQO1 as well as mitochondrial GSH, and that such upregulated endogenous defenses are accompanied by increased resistance to oxidative and electrophilic neurocytotoxicity.

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Oxidative stress and antioxidant therapy in Parkinson's disease

Cited by 305 publications

References 182 publications

Nanomicellar formulation of coenzyme Q10 (Ubisol-Q10) effectively blocks ongoing neurodegeneration in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model: potential use as an adjuvant treatment in Parkinson's disease

Nanomicellar formulation of coenzyme Q10 (Ubisol-Q10) effectively blocks ongoing neurodegeneration in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model: potential use as an adjuvant treatment in Parkinson's disease

Neuroprotective actions of selegiline

Potent induction of total cellular GSH and NQO1 as well as mitochondrial GSH by 3H-1,2-dithiole-3-thione in SH-SY5Y neuroblastoma cells and primary human neurons: Protection against neurocytotoxicity elicited by dopamine, 6-hydroxydopamine, 4-hydroxy-2-nonenal, or hydrogen peroxide

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