The hydroxycarboxylic acid receptor HCA2 is required for the protective effect of ketogenic diet in epilepsy.

Autor: Richardson JC; Neurosciences Therapeutic Area Unit, GlaxoSmithKline R&D Ltd, Stevenage, UK., Higgins GA; InterVivo Solutions, Toronto, Canada., Upton N; Transpharmation Ltd., South Mimms, UK., Massey P; Institute of Neuroscience, University of Newcastle, Newcastle, UK., Cunningham M; Institute of Neuroscience, University of Newcastle, Newcastle, UK.; Discipline of Physiology, School of Medicine, Trinity College Dublin, Dublin 2, Ireland., Wilson S; In vitro and in vivo Translation, GlaxoSmithKline R&D Ltd, Stevenage, UK., Holenz J; Neurosciences Therapeutic Area Unit, GlaxoSmithKline R&D Ltd, Upper Providence, Pennsylvania, USA., Taylor C; Transpharmation Ltd., South Mimms, UK., Lavrov A; Neurosciences Therapeutic Area Unit, GlaxoSmithKline R&D Ltd, Stockley Park, UK., Lin H; Neurosciences Therapeutic Area Unit, GlaxoSmithKline R&D Ltd, Upper Providence, Pennsylvania, USA., Matsuoka Y; Neurosciences Therapeutic Area Unit, GlaxoSmithKline R&D Ltd, Upper Providence, Pennsylvania, USA., Brown AJ; Medicine Design, GlaxoSmithKline R&D Ltd, Stevenage, UK.
Jazyk: angličtina
Zdroj: Pharmacology research & perspectives [Pharmacol Res Perspect] 2024 Dec; Vol. 12 (6), pp. e70026.
DOI: 10.1002/prp2.70026
Abstrakt: One third of epilepsy patients are resistant to treatment with current anti-seizure medications. The ketogenic diet is used to treat some forms of refractory epilepsy, but the mechanism of its action has not yet been elucidated. In this study, we aimed to investigate whether the hydroxycarboxylic acid receptor 2 (HCA2), a known immunomodulatory receptor, plays a role in mediating the protective effect of this diet. We demonstrate for the first time that selective agonists at this receptor can directly reduce seizures in animal models. Agonists also reduce network activity in rodent and human brain slices. Ketogenic diet is known to increase circulating levels of endogenous HCA2 agonists, and we show that the effect of ketogenic diet in reducing seizures in the 6 Hz seizure model is negated in HCA2-deficient mice. Our data support the potential of HCA2 as a target for the treatment of epilepsy and potentially for neurodegenerative diseases.
(© 2024 GSK. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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