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

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 ± 0.3mM for the treated group, 1.4 ± 0.1mM for the control group). This result suggests that ketone esters may pave the road towards the establishment of a "ketogenic diet in a pill".

Ketone Bodies as Anti-Seizure Agents

“…In contrast, administration of the ketone ester 1,3-butanediol did not affect seizure latencies, despite elevations in blood BHB levels. In further support of ketone esters as anti-seizure compounds, single or repeated dosing of BD-AcAc2 has been shown to increase the threshold for PTZ-induced seizures in rats [28, 29]. Taken together, these and other studies support the notion that KB can exert anti-seizure effects, separate from their role in ATP production, and likely through novel mechanisms, the most important of which are described below and depicted in Fig.…”

Use of the Ketogenic Diet to Treat Intractable Epilepsy in Mitochondrial Disorders

“…Research interest is also centred around the possibility of replacing the strict diet with its challenging adherence rules with supplements, like a “ketogenic pill”. Ketone esters given orally were effective anticonvulsants in mouse models of Angelmans and in pentylenetetrazole-model of seizures [64,65]. In addition, in Sada et al, lactate dehydrogensae (LDH) inhibition was seen to be effective in suppressing seizures.…”

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

“…It remains unclear whether the anti-convulsant effect is primarily attributable to ketone bodies, or due to the cascade metabolic consequences of low carbohydrate diets. Nonetheless, ketone esters (see below) appear to elevate the seizure threshold in animal models of provoked seizures (Ciarlone et al, 2016; D'Agostino et al, 2013; Viggiano et al, 2015). …”