Acetoacetate, Acetone, and Dibenzylamine (a Contaminant in l‐(+)‐β‐Hydroxybutyrate) Exhibit Direct Anticonvulsant Actions in Vivo

Abstract

Summary:Purpose: To investigate whether ketone bodies are directly anticonvulsant.Methods: We tested the effects of acetoacetate (ACA), acetone, and both stereoisomers, D-(−)-and L-(+), of ␤-hydroxybutyrate (BHB) on sensory-evoked seizures in Frings audiogenic seizure-susceptible mice.Results: We found that these ketone bodies, with the exception of the D-(−)-isomer of BHB, were anticonvulsant in this model. Furthermore, with gas chromatography-mass spectrometry, we confirmed that the activity of L-(+)-BHB was due to dibenzylamine, a chemical contaminant.Conclusions: Our data indicate that the anticonvulsant efficacy of the ketogenic diet may be due in part to the direct actions of ACA and acetone.

The Neuropharmacology of the Ketogenic Diet

“…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]. It is also active against audiogenic seizures in the Frings mouse [17].…”

“…Studies of the effects of the ketogenic diet on pentylenetetrazol threshold in rats have failed to show an association between plasma β-hydroxybutyrate levels and seizure threshold [16]. Moreover, exogenously administered β-hydroxybutyrate is not anticonvulsant in animal models such as the Frings audiogenic seizure-susceptible mouse [17].…”

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.…”

Age-related changes in the diurnal variation of ketogenesis in patients with type 2 diabetes and relevance to hypoglycemic medications

“…The means and SDs of the 3HB and FFA levels were calculated after logarith- [4][5][6][7]. In an animal model of epilepsy, an intraperitoneal injection of acetoacetate was protective against seizures [8]. Ketosis was neuroprotective in ischemic rat brains after reversible middle cerebral artery occlusion [9].…”