[Ketogenic diet may control seizures by increasing the binding potential of the benzodiazepine receptor: a speculation from the [11C] flumazenil-PET study].

The ketogenic diet (KD) is a high-fat, low-protein, low-carbohydrate diet which is effective in the treatment of medically refractory epilepsy. Several theories have been proposed to explain the mechanism underlying the anticonvulsant efficacy of the KD, however, the precise anticonvulsant mechanism of the KD is still unknown. We speculated the mechanism underlying the effect of the KD in patients with intractable epilepsy, based on the results of the [11C] flumazenil (FMZ)-positron emission tomography (PET) study. A patient developed frontal lobe epilepsy at the age of 2 years. At the age of 4 years 11 months, she was admitted to our hospital for the initiation of a KD. At the time of admission, she had several epileptic attacks each day: frequent postural tonic seizures, hypermotor seizures, head nodding, and intermittent loss of consciousness (non-convulsive status epilepticus). MR imaging showed no abnormal signal intensity in the brain. With the KD, the seizure frequency reduced dramatically on the fifth day. Interictal [11C] FMZ-PET was performed before and 2 months after the initiation of the KD. Before the KD, the [11C] FMZ-PET images and [11C] FMZ-PET binding potential (BP) images showed extremely low accumulation of FMZ throughout the cerebral cortex. Two months after the initiation of the KD, significantly increased binding potential of [11C] FMZ was observed, implying the increased binding potential of the benzodiazepine receptors, probably due to the anticonvulsant effect of the KD. These PET findings suggested that KD may control seizures by directly or indirectly increasing the binding potential of the benzodiazepine receptors.

Rats harboring S284L Chrna4 mutation show attenuation of synaptic and extrasynaptic GABAergic transmission and exhibit the nocturnal frontal lobe epilepsy phenotype.

Mutations of genes encoding alpha4, beta2, or alpha2 subunits (CHRNA4, CHRNB2, or CHRNA2, respectively) of nAChR [neuronal nicotinic ACh (acetylcholine) receptor] cause nocturnal frontal lobe epilepsy (NFLE) in human. NFLE-related seizures are seen exclusively during sleep and are characterized by three distinct seizure phenotypes: "paroxysmal arousals," "paroxysmal dystonia," and "episodic wandering." We generated transgenic rat strains that harbor a missense mutation S284L, which had been identified in CHRNA4 in NFLE. The transgenic rats were free of biological abnormalities, such as dysmorphology in the CNS, and behavioral abnormalities. The mRNA level of the transgene (mutant Chrna4) was similar to the wild type, and no distorted expression was detected in the brain. However, the transgenic rats showed epileptic seizure phenotypes during slow-wave sleep (SWS) similar to those in NFLE exhibiting three characteristic seizure phenotypes and thus fulfilled the diagnostic criteria of human NFLE. The therapeutic response of these rats to conventional antiepileptic drugs also resembled that of NFLE patients with the S284L mutation. The rats exhibited two major abnormalities in neurotransmission: (1) attenuation of synaptic and extrasynaptic GABAergic transmission and (2) abnormal glutamate release during SWS. The currently available genetically engineered animal models of epilepsy are limited to mice; thus, our transgenic rats offer another dimension to the epilepsy research field.