Kovács Zsolt, D'Agostino Dominic P, Dobolyi Arpád, Ari Csilla
Savaria Department of Biology, Eötvös Loránd UniversityBudapest, Hungary.
Hyperbaric Biomedical Research Laboratory, Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, TampaFL, United States.
Front Mol Neurosci. 2017 Jul 25;10:235. doi: 10.3389/fnmol.2017.00235. eCollection 2017.
The state of therapeutic ketosis can be achieved by using the ketogenic diet (KD) or exogenous ketone supplementation. It was suggested previously that the adenosinergic system may be involved in the mediating effect of KD on suppressing seizure activity in different types of epilepsies, likely by means of adenosine A receptors (ARs). Thus, we tested in the present study whether exogenous ketone supplements (ketone ester: KE, 2.5 g/kg/day; ketone salt/KS + medium chain triglyceride/MCT: KSMCT, 2.5 g/kg/day) applied sub-chronically (for 7 days) by intragastric gavage can modulate absence epileptic activity in genetically absence epileptic Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. The number of spike-wave discharges (SWDs) significantly and similarly decreased after both KE and KSMCT treatment between 3rd and 7th days of gavage. Moreover, blood beta-hydroxybutyrate (βHB) levels were significantly increased alike after KE and KSMCT gavage, compared to control levels. The SWD number and βHB levels returned to the baseline levels on the first day without ketone supplementation. To determine whether ARs can modify ketone supplement-evoked changes in absence epileptic activity, we applied a non-pro-epileptic dose of a specific AR antagonist DPCPX (1,3-dipropyl-8-cyclopentylxanthine) (intraperitoneal/i.p. 0.2 mg/kg) in combination with KSMCT (2.5 g/kg/day, gavage). As expected, DPCPX abolished the KSMCT-evoked decrease in SWD number. Thus, we concluded that application of exogenous ketone supplements may decrease absence epileptic activity in WAG/Rij rats. Moreover, our results suggest that among others the adenosinergic system, likely ARs, may modulate the exogenous ketone supplements-evoked anti-seizure effects.
通过采用生酮饮食（KD）或补充外源性酮类物质可实现治疗性酮症状态。此前有研究表明，腺苷能系统可能参与了KD对不同类型癫痫发作活动抑制作用的介导过程，可能是通过腺苷A受体（ARs）来实现的。因此，在本研究中，我们测试了通过胃内灌胃亚慢性（持续7天）给予外源性酮类补充剂（酮酯：KE，2.5 g/kg/天；酮盐/KS + 中链甘油三酯/MCT：KSMCT，2.5 g/kg/天）是否能调节遗传性失神癫痫Wistar白化Glaxo/Rijswijk（WAG/Rij）大鼠的失神癫痫活动。在灌胃的第3天至第7天，KE和KSMCT治疗后棘波-慢波放电（SWDs）的数量均显著且相似地减少。此外，与对照水平相比，KE和KSMCT灌胃后血中β-羟基丁酸（βHB）水平均显著升高。在不补充酮类物质的第一天，SWD数量和βHB水平恢复到基线水平。为了确定ARs是否能改变酮类补充剂引起的失神癫痫活动变化，我们将非癫痫发作剂量的特异性AR拮抗剂DPCPX（1,3-二丙基-8-环戊基黄嘌呤）（腹腔注射/i.p. 0.2 mg/kg）与KSMCT（2.5 g/kg/天，灌胃）联合应用。正如预期的那样，DPCPX消除了KSMCT引起的SWD数量减少。因此，我们得出结论，应用外源性酮类补充剂可能会减少WAG/Rij大鼠的失神癫痫活动。此外，我们的结果表明，除其他因素外，腺苷能系统，可能是ARs，可能调节外源性酮类补充剂引起的抗癫痫作用。
