A double‐blind, placebo‐controlled study to assess the mitochondria‐targeted antioxidant MitoQ as a disease‐modifying therapy in Parkinson's disease

Snow, Barry; Rolfe, Fiona L.; Lockhart, Michelle; Frampton, Christopher M.; O’Sullivan, John D.; Fung, Victor S.C.; Smith, Robin A.J.; Murphy, Michael P.; Taylor, Kenneth M.

doi:10.1002/mds.23148

Cited by 510 publications

(350 citation statements)

References 31 publications

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“…However, the relevance of such studies to the human condition remains uncertain, because acute neurotoxins are rarely the culprit in the majority of PD cases. This potential discrepancy is highlighted by a number of failed clinical trials that have heavily relied on toxin models as preclinical evidence for efficacy (13)(14)(15)(16). A more representative model of DA loss that uses known factors in human PD is likely vital to develop better therapeutic outcomes.…”

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confidence: 99%

Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson disease

Rousseaux

Marcogliese

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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DJ-1 mutations cause autosomal recessive early-onset Parkinson disease (PD). We report a model of PD pathology: the DJ1-C57 mouse. A subset of DJ-1–nullizygous mice, when fully backcrossed to a C57BL/6J background, display dramatic early-onset unilateral loss of dopaminergic (DA) neurons in their substantia nigra pars compacta , progressing to bilateral degeneration of the nigrostriatal axis with aging. In addition, these mice exhibit age-dependent bilateral degeneration at the locus ceruleus nucleus and display mild motor behavior deficits at aged time points. These findings effectively recapitulate the early stages of PD. Therefore, the DJ1-C57 mouse provides a tool to study the preclinical aspects of neurodegeneration. Importantly, by exome sequencing, we identify candidate modifying genes that segregate with the phenotype, providing potentially critical clues into how certain genes may influence the penetrance of DJ-1–related degeneration in mice.

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confidence: 99%

Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson disease

Rousseaux

Marcogliese

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…To date, the utilities of a therapeutic strategy using MitoQ have been demonstrated in in vivo experiments using various disease model animals [15,[34][35][36]. Moreover, MitoQ has been investigated in clinical trials [20,37,38] and is expected to be promising candidate for a mitochondrial medicine. MitoQ was also investigated for protection of the liver and heart from I/R injury in in vivo experiments using I/R injury induced mice and rats [15,39,40].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial delivery of Coenzyme Q10 via systemic administration using a MITO-Porter prevents ischemia/reperfusion injury in the mouse liver

Yamada

Nakamura

Abe

et al. 2015

Journal of Controlled Release

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We herein report on a mitochondrial therapeutic effect based on the delivery of coenzyme Q10 (CoQ10), an anti-oxidant, to in vivo mitochondria using a MITO-Porter, a liposome-based mitochondrial delivery system that functions via membrane fusion. To evaluate the effects, we used a mouse liver ischemia/reperfusion injury (I/R injury) model, in which mitochondrial reactive oxygen species are overexpressed. We packaged CoQ10 in the lipid phase of a MITO-Porter and optimized the mitochondrial fusogenic activities to produce the CoQ10-MITO-Porter. A histological observation of the carriers in the liver by confocal laser scanning microscopy was done and the accumulation of the carrier labeled with a radio isotope in the liver confirmed that the CoQ10-MITO-Porter was delivered to liver mitochondria via systemic injection. These analytical results permitted us to optimize the compositions of the CoQ10-MITO-Porter so as to permit it to efficiently accumulate in mouse liver mitochondria.Finally, we applied the optimized CoQ10-MITO-Porter to mice via tail vein injection, and hepatic I/R injury was then induced, followed by measuring serum alanine aminotransferase (ALT) levels, a marker of liver injury. We confirmed that the use of the CoQ10-MITO-Porter resulted in a significant decrease in serum ALT levels, indicating that in vivo mitochondrial delivery of the CoQ10 via MITO-Porter prevents I/R injury in mice livers. This provides a demonstration of the potential use of such a delivery system in mitochondrial therapies.

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“…Others have shown that targeting CoQ 10 to mitochondria by mitoquinone, designed based on the premises that offsetting mitochondria-generated oxidative stress will protect dopaminergic neurons did not achieve this goal. A clinical trial involving 128 newly diagnosed PD patients receiving either 40 or 80 mg/day mitoquinone for over 12 months failed to slow the progression of PD as measured by the Unified Parkinson's Disease Rating Scale (Snow et al, 2010).…”

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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A double‐blind, placebo‐controlled study to assess the mitochondria‐targeted antioxidant MitoQ as a disease‐modifying therapy in Parkinson's disease

Cited by 510 publications

References 31 publications

Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson disease

Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson disease

Mitochondrial delivery of Coenzyme Q10 via systemic administration using a MITO-Porter prevents ischemia/reperfusion injury in the mouse liver

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

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