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

IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pharmacology Research & Perspectives Pub Date : 2024-12-01 DOI:10.1002/prp2.70026
Jill C Richardson, Guy A Higgins, Neil Upton, Peter Massey, Mark Cunningham, Steve Wilson, Joerg Holenz, Colleen Taylor, Arseniy Lavrov, Hong Lin, Yasuji Matsuoka, Andrew J Brown
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Abstract

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.

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生酮饮食对癫痫的保护作用需要羟基羧酸受体 HCA2。
三分之一的癫痫患者对目前的抗癫痫药物产生抗药性。生酮饮食可用于治疗某些形式的难治性癫痫,但其作用机制尚未阐明。在这项研究中,我们旨在调查羟基羧酸受体 2(HCA2)--一种已知的免疫调节受体--是否在介导这种饮食的保护作用中发挥作用。我们首次证明,该受体的选择性激动剂可直接减少动物模型的癫痫发作。激动剂还能减少啮齿动物和人类大脑切片的网络活动。众所周知,生酮饮食会增加内源性 HCA2 激动剂的循环水平,而我们的研究表明,在 6 Hz 癫痫发作模型中,生酮饮食在减少癫痫发作方面的作用在 HCA2 缺陷小鼠中被否定了。我们的数据支持 HCA2 作为治疗癫痫和潜在神经退行性疾病靶点的潜力。
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来源期刊
Pharmacology Research & Perspectives
Pharmacology Research & Perspectives Pharmacology, Toxicology and Pharmaceutics-General Pharmacology, Toxicology and Pharmaceutics
CiteScore
5.30
自引率
3.80%
发文量
120
审稿时长
20 weeks
期刊介绍: PR&P is jointly published by the American Society for Pharmacology and Experimental Therapeutics (ASPET), the British Pharmacological Society (BPS), and Wiley. PR&P is a bi-monthly open access journal that publishes a range of article types, including: target validation (preclinical papers that show a hypothesis is incorrect or papers on drugs that have failed in early clinical development); drug discovery reviews (strategy, hypotheses, and data resulting in a successful therapeutic drug); frontiers in translational medicine (drug and target validation for an unmet therapeutic need); pharmacological hypotheses (reviews that are oriented to inform a novel hypothesis); and replication studies (work that refutes key findings [failed replication] and work that validates key findings). PR&P publishes papers submitted directly to the journal and those referred from the journals of ASPET and the BPS
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