1. A new ketogenic formulation improves functional outcome and reduces tissue loss following traumatic brain injury in adult mice
- Author
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Jordi L. Tremoleda, J Martin Verkuyl, Susanne Lotstra, René G. Feichtinger, Adina T. Michael-Titus, Jose P. Silva, Nick van Wijk, Robert J.J. Hageman, Laus M. Broersen, Linda Svendsen, Molly Rhodes, Barbara Kofler, Ursula Paredes-Esquivel, John V. Priestley, Simon C. Dyall, and Orli Thau-Zuchman
- Subjects
0301 basic medicine ,Dietary Fiber ,Male ,epigenetic modifications ,medicine.medical_treatment ,Lameness, Animal ,Medicine (miscellaneous) ,Epigenesis, Genetic ,Adult traumatic brain injury ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Morris Water Maze Test ,Brain Injuries, Traumatic ,neurological outcome ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Postural Balance ,Spatial Memory ,Ketogenic amino acid ,3-Hydroxybutyric Acid ,TOR Serine-Threonine Kinases ,Brain ,Acetylation ,Histone Code ,Paresis ,Oligodendroglia ,medicine.anatomical_structure ,ketogenic diet ,Docosahexaenoic acid ,Sensation Disorders ,neuroprotection ,Dietary Proteins ,medicine.symptom ,Diet, Ketogenic ,Research Paper ,Signal Transduction ,medicine.medical_specialty ,Docosahexaenoic Acids ,Traumatic brain injury ,Inflammation ,Neuroprotection ,Methylation ,Lesion ,03 medical and health sciences ,Leucine ,Internal medicine ,medicine ,Dietary Carbohydrates ,Animals ,Triglycerides ,business.industry ,medicine.disease ,Dietary Fats ,Oligodendrocyte ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,chemistry ,Glycemic Index ,Rotarod Performance Test ,Ataxia ,business ,030217 neurology & neurosurgery ,Ketogenic diet - Abstract
Rationale: Traumatic brain injury (TBI) leads to neurological impairment, with no satisfactory treatments available. Classical ketogenic diets (KD), which reduce reliance on carbohydrates and provide ketones as fuel, have neuroprotective potential, but their high fat content reduces compliance, and experimental evidence suggests they protect juvenile brain against TBI, but not adult brain, which would strongly limit their applicability in TBI. Methods: We designed a new-KD with a fat to carbohydrate plus protein ratio of 2:1, containing medium chain triglycerides (MCT), docosahexaenoic acid (DHA), low glycaemic index carbohydrates, fibres and the ketogenic amino acid leucine, and evaluated its neuroprotective potential in adult TBI. Adult male C57BL6 mice were injured by controlled cortical impact (CCI) and assessed for 70 days, during which they received a control diet or the new-KD. Results: The new-KD, that markedly increased plasma Beta-hydroxybutyrate (β-HB), significantly attenuated sensorimotor deficits and corrected spatial memory deficit. The lesion size, perilesional inflammation and oxidation were markedly reduced. Oligodendrocyte loss appeared to be significantly reduced. TBI activated the mTOR pathway and the new-KD enhanced this increase and increased histone acetylation and methylation. Conclusion: The behavioural improvement and tissue protection provide proof of principle that this new formulation has therapeutic potential in adult TBI.
- Published
- 2020