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. 2024 Dec;60(11):6875-6890.
doi: 10.1111/ejn.16601. Epub 2024 Nov 11.

Ketone ester-enriched diet ameliorates motor and dopamine release deficits in MitoPark mice

Vikrant R Mahajan  1   2 , Jacob A Nadel  1 , M Todd King  2 , Robert J Pawlosky  2 , Margaret I Davis  1 , Richard L Veech  2 , David M Lovinger  1 , Armando G Salinas  1   3
Affiliations

Ketone ester-enriched diet ameliorates motor and dopamine release deficits in MitoPark mice

Vikrant R Mahajan et al. Eur J Neurosci. 2024 Dec.

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.

Keywords: Parkinson's disease; dopamine neurons; ketosis; neuroprotection; striatum.

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Conflict of interest statement

RLV and MTK received royalties from patents owned by The National Institutes of Health, Oxford University, and TdeltaS Ltd., a University of Oxford company, established to commercialize the ketone ester. All other authors declare no financial interests or potential conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Comparison of ketone ester–enriched diets (KEEDs). (a) Macronutrient composition of tested KEEDs. Mice were fed each KEED for 30 days with body weights (b) and blood ketone levels (c) assessed periodically. n = 4 mice per diet group.
FIGURE 2
FIGURE 2
Presymptomatic KEED treatment ameliorated motor deficits in MitoPark mice. (a) Experimental timeline illustrating behavioral testing and diet onset. (b–d) Mice were tested in an open field to assess locomotion. MitoPark mice fed the SD exhibited decreased locomotion compared to MitoPark mice fed the 16% KEED (d). Mice were further tested in the rotarod apparatus (e). MitoPark mice fed the SD performed progressively worse (f) than KEED MitoPark and control mice (g). n = 10–14 mice per group. ***p < 0.001; n.s. p > 0.1. KEED, ketone ester–enriched diet; n.s., no significance; SD, standard diet.
FIGURE 3
FIGURE 3
Progressive decrease in dopamine release in MitoPark mice is ameliorated by KEED. (a) Schematic for fast‐scan cyclic voltammetry experiments. (b) Representative dopamine release data for each group at 20 weeks. At 5 weeks (c), dopamine release did not differ between genotypes. (d) At 10 weeks, dopamine release was decreased in MitoPark mice. (e) At 20 weeks, dopamine release was decreased in MitoPark relative to control mice in SD groups. (f) MitoPark mice fed the KEED had greater dopamine release than MitoPark mice fed the SD. n = 7–12 slices per group from 5 to 7 mice per group. ***p < 0.001. KEED, ketone ester–enriched diet; SD, standard diet.
FIGURE 4
FIGURE 4
KEED does not preserve dopamine neurons or striatal axon loss in 20‐week‐old MitoPark mice. (a) Representative immunohistochemistry images of dorsal striatum (upper row) and midbrain dopamine neurons (lower row). (b) Striatal tyrosine hydroxylase‐immunoreactivity and midbrain dopamine neurons (c) were decreased in both MitoPark groups. Dopamine (d) and DOPAC (e) content were decreased in dorsal striatal tissue from 20‐week‐old MitoPark mice relative to controls. DOPAC/dopamine ratios (f) did not differ significantly across groups. n = 4 mice per group for immunohistochemistry experiments and n = 7–12 mice per group for biochemistry experiments. **p < 0.01; ***p < 0.001. KEED, ketone ester–enriched diet.
FIGURE 5
FIGURE 5
Beginning ketone ester enriched diet after motor deficit onset may slow progressive motor dysfunction in MitoPark mice. (a) Experimental timeline illustrating behavioral testing and KEED onset. (b, c) MitoPark mice fed either diet exhibited decreased locomotion in the open field relative to control groups. (d, e) MitoPark mice fed the control diet performed progressively worse on the rotarod across the study (d). MitoPark mice fed the KEED had improved motor function initially but failed to maintain this improvement. n = 5–7 mice per group. *p < 0.05; ***p < 0.001. KEED, ketone ester–enriched diet.
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