Anticonvulsant properties of acetone, a brain ketone elevated by the ketogenic diet.
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.
Likhodii
Sergei S
SS
Department of Pharmacology, Faculty of Medicine, University of Toronto, Ontario, Canada. sergei.likhodi@utoronto.ca
Serbanescu
Irina
I
Cortez
Miguel A
MA
Murphy
Patricia
P
Snead
O Carter
OC
Burnham
W McIntyre
WM
D000096:Acetone / Q000378:metabolism / Q000494:pharmacology*; D000679:Amygdala / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants; D001259:Ataxia / Q000139:chemically induced / Q000523:psychology; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology*; D003292:Convulsants; D003920:Diabetes Mellitus / Q000178:diet therapy; D004032:Diet; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D004832:Epilepsy, Absence / Q000139:chemically induced / Q000188:drug therapy; D017029:Epilepsy, Complex Partial / Q000139:chemically induced / Q000188:drug therapy; D004830:Epilepsy, Tonic-Clonic / Q000139:chemically induced / Q000188:drug therapy; D007696:Kindling, Neurologic / Q000502:physiology; D008297:Male; D010433:Pentylenetetrazole; D051381:Rats; D017208:Rats, Wistar; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride / Q000494:pharmacology
D000927:Anticonvulsants; D003292:Convulsants; D000096:Acetone; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride; D010433:Pentylenetetrazole