Theranostics 2021; 11(1):346-360. doi:10.7150/thno.48995

Research Paper

A new ketogenic formulation improves functional outcome and reduces tissue loss following traumatic brain injury in adult mice

Orli Thau-Zuchman1✉, Linda Svendsen1, Simon C. Dyall2, Ursula Paredes-Esquivel1, Molly Rhodes1, John V. Priestley1, René G. Feichtinger3, Barbara Kofler3, Susanne Lotstra4, J. Martin Verkuyl4, Robert J. Hageman4, Laus M. Broersen4, Nick van Wijk4, Jose P. Silva2, Jordi L. Tremoleda1, Adina T. Michael-Titus1

1. Centre for Neuroscience, Surgery and Trauma, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, Whitechapel, London, E1 2AT, UK.
2. University of Roehampton, Department of Life Sciences, Grove House, Roehampton Lane, London, SW15 5PJ, UK.
3. Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Müllner Hauptstrasse 48, A-5020, Salzburg, Austria.
4. Danone Nutricia Research, Uppsalalaan 12, Utrecht, 3584 CT, The Netherlands.

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Citation:
Thau-Zuchman O, Svendsen L, Dyall SC, Paredes-Esquivel U, Rhodes M, Priestley JV, Feichtinger RG, Kofler B, Lotstra S, Verkuyl JM, Hageman RJ, Broersen LM, van Wijk N, Silva JP, Tremoleda JL, Michael-Titus AT. A new ketogenic formulation improves functional outcome and reduces tissue loss following traumatic brain injury in adult mice. Theranostics 2021; 11(1):346-360. doi:10.7150/thno.48995. Available from https://www.thno.org/v11p0346.htm

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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.

Keywords: Adult traumatic brain injury, epigenetic modifications, ketogenic diet, neurological outcome, neuroprotection