Abstracts

([italic]R,S[/italic])-1,3-Butanediol (1,3-BD) is a common food additive that has a long history of safety in various species. 1,3-BD is metabolized by alcohol and aldehyde dehydrogenases in the liver to form [beta]-hydroxybutyrate, acetoacetate, and acetone, which are the same ketone bodies whose levels are elevated in the ketogenic diet. Here we sought to determine if 1,3-BD has anticonvulsant effects and could potentially be a replacement for the ketogenic diet., The anticonvulsant activity of 1,3-BD was assessed in several in vitro and in vivo models. Acute toxicity was determined in the inverted-screen test. To determine the contribution of ketosis to the anticonvulsant efficacy of 1,3-BD, animals were pretreated with the alcohol dehydrogenase inhibitor 4-methylpyrazole. In addition, we used the [italic]R[/italic]- and [italic]S[/italic]-enantiomers of 1,3-BD since only the [italic]R[/italic]-enantiomer can be directly converted to acetone., 1,3-BD attenuated epileptiform activity induced by 4-aminopyridine (55 [micro]M) in rat hippocampal slices in a concentration-dependent manner (10[ndash]100 mM). Furthermore, 1,3-BD (1[ndash]32 mmol/kg, IP) demonstrated a broad anticonvulsant profile in a variety of seizure tests in mice (iv PTZ test, electroconvulsive threshold, 6-Hz seizure model) and rats (amygdala-kindled seizures). The anticonvulsant effects of 1,3-BD occurred at doses devoid of acute toxicity. After the administration of an anticonvulsant dose of 1,3-BD, levels of the ketone body, [beta]-hydroxybutyrate, were comparable to those seen in mice exposed to the ketogenic diet for several weeks. Inhibition of 1,3-BD conversion to ketone bodies by 4-methylpyrazole (25 mg/kg) augmented the anticonvulsant effects of 1,3-BD, indicating that 1,3-BD itself has anticonvulsant activity. Like the racemic form of 1,3-BD, the [italic]R[/italic]- and [italic]S[/italic]-enantiomers individually demonstrated robust anticonvulsant properties, demonstrating that conversion to ketone bodies is not required for seizure protection. However, the [italic]R[/italic]-enantiomer was modestly more potent suggesting that ketone bodies could contribute to the anticonvulsant activity., 1,3-BD and its enantiomers are protective in a broad range of seizure models. Conversion to ketone bodies is not required for efficacy, but could augment the activity of the parent. Further studies are required to assess the potential of 1,3-BD or its enantiomers in the treatment of epilepsy., (Supported by NINDS/NIH.)