Anticonvulsant properties of acetone, a brain ketone elevated by the ketogenic diet

Abstract

The ketogenic diet (KD), a treatment for drug-resistant epilepsy, elevates brain acetone. Acetone has been shown to suppress experimental seizures. Whether elevation of acetone is the basis of the anticonvulsant effects of the KD and whether acetone, like the KD, antagonizes many different types of seizures, however, is unknown. This study investigated the spectrum of the anticonvulsant effects of acetone in animal seizure models. Rats were injected with acetone intraperitoneally. Dose-response effects were measured in four different models: (1) the maximal electroshock test, which models human tonic-clonic seizures; (2) the subcutaneous pentylenetetrazole test, which models human typical absence seizures; (3) the amygdala kindling test, which models human complex partial seizures with secondary generalization; and (4) the AY-9944 test, which models chronic atypical absence seizures, a component of the Lennox-Gastaut syndrome. Acetone suppressed seizures in all of the models, with the following ED(50)'s (expressed in mmol/kg): maximal electroshock, 6.6; pentylenetetrazole, 9.7; generalized kindled seizures, 13.1; focal kindled seizures, 26.5; AY-9944, 4.0. Acetone appears to have a broad spectrum of anticonvulsant effects. These effects parallel the effects of the KD. Elevation of brain acetone therefore may account for the efficacy of the KD in intractable epilepsy.

The Neuropharmacology of the Ketogenic Diet

“…In rats, these metabolites are protective against seizures induced by pentylenetetrazol and AY-9944 (an inhibitor of the biosynthesis of cholesterol that induces slow spike-and-wave discharges and is proposed as a model of chronic atypical absence seizures). Acetone is also protective in the maximal electroshock test [19] and the amygdala kindling model [19]. In mice, acetone protects against clonic seizures induced by pentylenetetrazol, as is the case in rats, and it also is protective against tonic seizures induced by 4-aminopyridine [20].…”

Fasting in mood disorders: neurobiology and effectiveness. A review of the literature

“…Finally, the production of ketone bodies could be involved in improving mood, decreasing pain sensation, and promoting neuro-neuronal protection against hypoglycemia and different types of brain damage (Brown, 2007;Maalouf et al, 2009;White et al, 2007) possibly through anticonvulsant properties (Gasior et al, 2007;Hasebe et al, 2010;Likhodii et al, 2003;Zarnowska et al, 2009). Further studies are needed to determine the role of ketone bodies in the neurobiological effects of fasting.…”

The Ketogenic Diet: Proposed Mechanisms of Action

“…In our hands, neither acetoacetate nor beta-hydroxybutyrate has shown anticonvulsant effects, 23 although see Rho et al 24 Acetone, however, as with ketogenic diet itself, has broad spectrum anticonvulsant effects. 23 It is effective against a variety of different seizure types and its anti-seizure effects are associated with little toxicity. 23 In animals, these effects occur at blood acetone concentrations from 1 to 30 mM.…”

“…23 It is effective against a variety of different seizure types and its anti-seizure effects are associated with little toxicity. 23 In animals, these effects occur at blood acetone concentrations from 1 to 30 mM.…”