Effects of GM1 ganglioside treatment on pre- and postsynaptic dopaminergic markers in the striatum of parkinsonian monkeys

Pope-Coleman, A.; Tinker, J.P.; Schneider, Jay S.

doi:10.1002/(sici)1098-2396(200005)36:2<120::aid-syn5>3.3.co;2-p

Cited by 6 publications

(6 citation statements)

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“…Exogenous administration of ganglioside GM1 or its synthetic derivatives has shown neuroprotective properties in models of neural injury by growth factor withdrawal (Ferrari et al, 1995) or excitotoxicity (Wu et al, 2004), as well as in primate models of Parkinson's disease (Pope-Coleman et al, 2000) and in stroke (Oppenheimer, 1990). In HD, where endogenous levels of the ganglioside are reduced, GM1 is likely to have multiple beneficial effects, by restoring normal ganglioside content and by targeting multiple aspects of the HD pathology: from cell signaling and AKT activation to mHtt phosphorylation, susceptibility to apoptosis, and potentially also axonal transport and neurotrophin release and excitotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Impaired Ganglioside Metabolism in Huntington's Disease and Neuroprotective Role of GM1

Maglione¹,

Marchi²,

Pardo³

et al. 2010

J. Neurosci.

124

152

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Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of a polyglutamine stretch in the protein huntingtin (Htt). HD neurons are dysfunctional at multiple levels and have increased susceptibility to stress and apoptotic stimuli. We have discovered that synthesis of the ganglioside GM1 is reduced in fibroblasts from HD patients and in cell and animal models of HD, and that decreased GM1 levels contribute to heighten HD cell susceptibility to apoptosis. The apoptotic susceptibility is recapitulated through inhibition of ganglioside synthesis in wild-type striatal cells, suggesting that decreased GM1 levels might be one of the key events leading to HD pathogenesis and progression. Administration of GM1 restores ganglioside levels in HD cells and promotes activation of AKT and phosphorylation of mutant Htt, leading to decreased mutant Htt toxicity and increased survival of HD cells. Our data identify GM1 as a potential treatment for HD.

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Section: Discussionmentioning

confidence: 99%

Impaired Ganglioside Metabolism in Huntington's Disease and Neuroprotective Role of GM1

Maglione¹,

Marchi²,

Pardo³

et al. 2010

J. Neurosci.

124

152

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“…GM1 protects against nigrostriatal toxicity and associated motor symptoms induced by 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine in mice and monkeys (171,(176)(177)(178). GM1 treatment restored cognitive and motor function and prevented decline in function in a 90 week trial in monkeys (179).…”

Section: Therapeutic Potentials Of Gangliosides In Patients With Admentioning

confidence: 99%

Thematic Review Series: Sphingolipids. Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease—a review

Ariga

McDonald

2008

Journal of Lipid Research

292

236

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“…1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been used extensively to model Parkinson's disease in species as diverse as monkeys, mice and worms (Braungart et al 2004;Pope-Coleman & Schneider 1998;Pope-Coleman et al 2000;Schneider & DiStefano 1994;Schneider & Yuwiler 1989;Schneider et al 1998). Injected systemically, it destroys nigrostriatal dopaminergic neurons rapidly and reliably.…”

mentioning

confidence: 99%

A single intramuscular injection of rAAV-mediated mutant erythropoietin protects against MPTP-induced parkinsonism

Dhanushkodi

Akano

Roguski

et al. 2012

Genes, Brain and Behavior

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Erythropoietin (Epo) is neuroprotective in a number of preparations, but can lead to unacceptably high and even lethal hematocrit levels. Recent reports show that modified Epo variants confer neuroprotection in models of glaucoma and retinal degeneration without raising hematocrit. In this study, neuroprotective effects of two Epo variants (EpoR76E and EpoS71E) were assessed in a model of Parkinson's disease. The constructs were packaged in recombinant adeno-associated viral (rAAV) vectors and injected intramuscularly. After 3 weeks, mice received five daily injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and were killed 5 weeks later. The MPTP-lesioned mice pretreated with rAAV.eGFP (negative control) exhibited a 7-to 9-Hz tremor and slower latencies to move on a grid test (akinesia). Both of these symptomatic features were absent in mice pretreated with either modified Epo construct. The rAAV.eGFP-treated mice lesioned with MPTP exhibited a 41% reduction in tyrosine hydroxylase (TH)-positive neurons in the substantia nigra. The rAAV.EpoS71E construct did not protect nigral neurons, but neuronal loss in mice pretreated with rAAV.EpoR76E was only half that of rAAV.eGFP controls. Although dopamine levels were normal in all groups, 3,4-dihydroxyphenylacetic acid (DOPAC) was significantly reduced only in MPTP-lesioned mice pre-treated with rAAV.eGFP, indicating reduced dopamine turnover. Analysis of TH-positive fibers in the striatum showed normalized density in MPTP-lesioned mice pretreated with rAAV.EpoS71E, suggesting that enhanced sprouting induced by EpoS71E may have been responsible for normal behavior and dopaminergic tone in these mice. These results show that systemically administered rAAV-generated nonerythropoietic Epo may protect against MPTP-induced parkinsonism by a combination of neuroprotection and enhanced axonal sprouting. Parkinson's disease is characterized neuropathologically by gradual degeneration of dopaminergic neurons in the substantia nigra and behaviorally by bradykinesia, akinesia, tremor, postural instability and impaired executive function (Blanchet et al. 2000;Monchi et al. 2007;Mondon et al. 2007). There is no cure for Parkinson's disease, and current interventions are typically directed toward diminishing behavioral symptoms and enhancing quality of life. The most commonly used treatments at the moment are only partially and transiently effective, or are only effective in a minority of patients (Bronstein et al. 2011;Poulopoulos & Waters 2010;Wood 2010). Importantly, they do not prevent the progressive destruction of nigrostriatal neurons. HHS Public Access1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been used extensively to model Parkinson's disease in species as diverse as monkeys, mice and worms (Braungart et al. 2004;Pope-Coleman & Schneider 1998;Pope-Coleman et al. 2000;Schneider & DiStefano 1994;Schneider & Yuwiler 1989;Schneider et al. 1998). Injected systemically, it destroys nigrostriatal dopaminergic neurons rapidly and reliably. The ...

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Effects of GM1 ganglioside treatment on pre- and postsynaptic dopaminergic markers in the striatum of parkinsonian monkeys

Cited by 6 publications

References 0 publications

Impaired Ganglioside Metabolism in Huntington's Disease and Neuroprotective Role of GM1

Impaired Ganglioside Metabolism in Huntington's Disease and Neuroprotective Role of GM1

Thematic Review Series: Sphingolipids. Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease—a review

A single intramuscular injection of rAAV-mediated mutant erythropoietin protects against MPTP-induced parkinsonism

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