Ketone ester–enriched diet ameliorates motor and dopamine release deficits in MitoPark mice
Abstract Parkinson's disease (PD) is a progressive, neurodegenerative disease characterized by motor dysfunction and dopamine deficits. The MitoPark (MP) mouse model of PD recapitulates several facets of Parkinson's disease, including gradual development of motor deficits, which enables th...
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| Published in | The European journal of neuroscience |
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| Main Authors | , , , , , , , |
| Format | Journal Article |
| Language | English |
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11.11.2024
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| Abstract | Abstract Parkinson's disease (PD) is a progressive, neurodegenerative disease characterized by motor dysfunction and dopamine deficits. The MitoPark (MP) mouse model of PD recapitulates several facets of Parkinson's disease, including gradual development of motor deficits, which enables the study of potential therapeutic interventions. One therapeutic strategy involves decreasing the mitochondrial metabolic load by inducing ketosis and providing an alternative energy source for neurons, leading to decreased neuronal oxidative stress. Thus, we hypothesized that administration of a ketone ester–enriched diet (KEED) would improve motor and dopamine release deficits in MP mice. Motor function (rotarod and open field tests), dopamine release (fast‐scan cyclic voltammetry), tissue dopamine levels (gas chromatography–mass spectrometry) and dopamine neurons and axons (immunofluorescence) were assessed in MP, and control mice fed either the standard or a KEED. When started on the ketone diet before motor dysfunction onset, MP mice had improved motor function relative to standard diet (SD) MP mice. While the KEED did not preserve dopamine neurons or striatal dopamine axons, dopamine release in ketone diet MP mice was greater than SD MP mice but less than control mice. In a follow‐up experiment, we began the ketone diet after motor dysfunction onset and observed a modest preservation of motor function in ketone diet MP mice relative to SD MP mice. The improvement in motor dysfunction indicates that a KEED or ketone supplement may have a beneficial effect on delaying motor deficit progression in Parkinson's disease. |
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| AbstractList | Abstract Parkinson's disease (PD) is a progressive, neurodegenerative disease characterized by motor dysfunction and dopamine deficits. The MitoPark (MP) mouse model of PD recapitulates several facets of Parkinson's disease, including gradual development of motor deficits, which enables the study of potential therapeutic interventions. One therapeutic strategy involves decreasing the mitochondrial metabolic load by inducing ketosis and providing an alternative energy source for neurons, leading to decreased neuronal oxidative stress. Thus, we hypothesized that administration of a ketone ester–enriched diet (KEED) would improve motor and dopamine release deficits in MP mice. Motor function (rotarod and open field tests), dopamine release (fast‐scan cyclic voltammetry), tissue dopamine levels (gas chromatography–mass spectrometry) and dopamine neurons and axons (immunofluorescence) were assessed in MP, and control mice fed either the standard or a KEED. When started on the ketone diet before motor dysfunction onset, MP mice had improved motor function relative to standard diet (SD) MP mice. While the KEED did not preserve dopamine neurons or striatal dopamine axons, dopamine release in ketone diet MP mice was greater than SD MP mice but less than control mice. In a follow‐up experiment, we began the ketone diet after motor dysfunction onset and observed a modest preservation of motor function in ketone diet MP mice relative to SD MP mice. The improvement in motor dysfunction indicates that a KEED or ketone supplement may have a beneficial effect on delaying motor deficit progression in Parkinson's disease. |
| Author | Pawlosky, Robert J. Veech, Richard L. Lovinger, David M. Nadel, Jacob A. Davis, Margaret I. Mahajan, Vikrant R. King, M. Todd Salinas, Armando G. |
| Author_xml | – sequence: 1 givenname: Vikrant R. surname: Mahajan fullname: Mahajan, Vikrant R. organization: Laboratory for Integrative Neuroscience National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health Rockville Maryland USA, Laboratory for Metabolic Control National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health Rockville Maryland USA – sequence: 2 givenname: Jacob A. surname: Nadel fullname: Nadel, Jacob A. organization: Laboratory for Integrative Neuroscience National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health Rockville Maryland USA – sequence: 3 givenname: M. Todd surname: King fullname: King, M. Todd organization: Laboratory for Metabolic Control National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health Rockville Maryland USA – sequence: 4 givenname: Robert J. surname: Pawlosky fullname: Pawlosky, Robert J. organization: Laboratory for Metabolic Control National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health Rockville Maryland USA – sequence: 5 givenname: Margaret I. surname: Davis fullname: Davis, Margaret I. organization: Laboratory for Integrative Neuroscience National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health Rockville Maryland USA – sequence: 6 givenname: Richard L. surname: Veech fullname: Veech, Richard L. organization: Laboratory for Metabolic Control National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health Rockville Maryland USA – sequence: 7 givenname: David M. surname: Lovinger fullname: Lovinger, David M. organization: Laboratory for Integrative Neuroscience National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health Rockville Maryland USA – sequence: 8 givenname: Armando G. orcidid: 0000-0002-1682-128X surname: Salinas fullname: Salinas, Armando G. organization: Laboratory for Integrative Neuroscience National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health Rockville Maryland USA, Department of Pharmacology, Toxicology & Neuroscience Louisiana State University Health Sciences Center – Shreveport Shreveport Louisiana USA |
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