Anticonvulsant properties of an oral ketone ester in a pentylenetetrazole-model of seizure

• Published in: Brain research Vol. 1618; pp. 50 - 54
• Main Authors: Viggiano, Andrea, Pilla, Raffaele, Arnold, Patrick, Monda, Marcellino, D׳Agostino, Dominic, Coppola, Giangennaro
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 27.08.2015
• Subjects: Acetoacetates - administration & dosage; Administration, Oral; Analysis of Variance; Animals; Anticonvulsants - administration & dosage; Butylene Glycols - administration & dosage; Convulsants - toxicity; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography; Ketogenic diet; Ketone ester; Male; Neurology; Pentylenetetrazole; Pentylenetetrazole - toxicity; Rats; Rats, Wistar; Seizure threshold; Seizures - chemically induced; Seizures - diet therapy; βHB; BD-AcAc2; 1,3-butanediol acetoacetate diester; cortical-electroencephalogram; Seizure threshold; β-hydroxybutyrate; cEEG; central nervous system oxygen toxicity; CNS-OT; ATA; Ketone ester; ANCOVA; acetoacetate; ketogenic diet; RNS; PTZ; pentylenetetrazole; ROS; reactive oxygen species; atmospheres absolute; KD; reactive nitrogen species; AcAc; analysis of covariance; Ketogenic diet; Pentylenetetrazole
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2015.05.023

Abstract The ketogenic diet is known to have an anti-epileptic effect; in fact it is currently used to treat drug resistant epilepsies. The efficacy of this diet is thought to be correlated to the elevation of blood ketone bodies. Because of problems with compliance to this diet, there is an interest in evaluating alternative pharmacological treatments that can have anti-seizure effects by elevating ketone bodies. In the present experiment, an orally administered synthetic ketone ester (R,S – 1,3-butanediol acetoacetate diester, or BD-AcAc2) was evaluated for its anti-seizure efficacy in a rat model. The threshold for seizure induction with progressive intravenous infusion of pentylenetrazole (PTZ) was evaluated in anesthetized Wistar rats two hours after a single 1 ml intragastric administration of BD-AcAc2 (i.e. 4 g/kg b.w., treated group) or water (control group). After correction for the dose of anesthetic, the results showed that the administration of BD-AcAc2 induced an elevation of the PTZ threshold (140±11 mg/kg for the treated group, 122±6 mg/kg for the control group), along with an increased level of blood β-hydroxybutyrate (2.7±0.3 mM for the treated group, 1.4±0.1 mM for the control group). This result suggests that ketone esters may pave the road towards the establishment of a “ketogenic diet in a pill”.