Multiple sclerosis and related disorders · 2026
Early myelin-associated histological and cellular findings following ketogenic diet or ketone ester treatment in a cuprizone/rapamycin mouse model.
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Alaeiilkhchi Nima, Zhou Wen, Jangjoo Ghalat Nasrin, Kolehmainen Kathleen, Thomson Tyler, Rajendran Anjana, Liu Jie, Seira Oscar, Tetzlaff Wolfram
Аннотация
BACKGROUND: Impaired restoration of CNS myelin contributes to progressive disability in multiple sclerosis (MS), yet current disease-modifying therapies do not directly target this biology. Metabolic interventions such as the ketogenic diet (KD) are of interest, but sustained dietary adherence may be limited.
METHODS: Male C57BL/6 mice underwent cuprizone/rapamycin demyelination for 6 weeks and, after an additional 7-day rapamycin washout with continued cuprizone exposure, received 9 days of standard diet (SD), ketogenic diet (KD), or intermittent ketone ester injections (iKE) during early recovery. Circulating β-hydroxybutyrate (βHB), lesion histology, oligodendrocyte lineage cells, plasma cytokines, and exploratory behavior were assessed.
RESULTS: Both KD and iKE resulted in higher sampled circulating βHB values than SD at selected time points and were associated with higher myelin basic protein (MBP) immunoreactivity than SD. Relative to SD, KD was associated with increased Iba1 immunoreactivity and reduced Oil Red O (ORO)-positive neutral lipid signal. iKE was associated with higher densities of Olig2⁺CC1⁺ mature oligodendrocytes and Olig2⁺BCAS1⁺ early myelinating oligodendrocytes, and with lower circulating TNF-α and IL-10. Exploratory behavioral outcomes did not differ significantly among treatment groups.
CONCLUSIONS: KD and iKE were associated with higher MBP immunoreactivity during early recovery without detected behavioral improvement over nine days. The accompanying cellular findings warrant further study of metabolic interventions in myelin repair; whether CNS ketone availability mediated these findings remains undetermined.
METHODS: Male C57BL/6 mice underwent cuprizone/rapamycin demyelination for 6 weeks and, after an additional 7-day rapamycin washout with continued cuprizone exposure, received 9 days of standard diet (SD), ketogenic diet (KD), or intermittent ketone ester injections (iKE) during early recovery. Circulating β-hydroxybutyrate (βHB), lesion histology, oligodendrocyte lineage cells, plasma cytokines, and exploratory behavior were assessed.
RESULTS: Both KD and iKE resulted in higher sampled circulating βHB values than SD at selected time points and were associated with higher myelin basic protein (MBP) immunoreactivity than SD. Relative to SD, KD was associated with increased Iba1 immunoreactivity and reduced Oil Red O (ORO)-positive neutral lipid signal. iKE was associated with higher densities of Olig2⁺CC1⁺ mature oligodendrocytes and Olig2⁺BCAS1⁺ early myelinating oligodendrocytes, and with lower circulating TNF-α and IL-10. Exploratory behavioral outcomes did not differ significantly among treatment groups.
CONCLUSIONS: KD and iKE were associated with higher MBP immunoreactivity during early recovery without detected behavioral improvement over nine days. The accompanying cellular findings warrant further study of metabolic interventions in myelin repair; whether CNS ketone availability mediated these findings remains undetermined.