A ketogenic diet and knockout of the norepinephrine transporter both reduce seizure severity in mice

Ketogenic diets (KD) have been known to be effective against epilepsy for more than 80 years, yet the mechanism(s) responsible for this action remain unknown. Norepinephrine (NE) has been shown to have anti-ictal effects against a wide variety of pro-convulsants and in animal models of epilepsy. Loss of noradrenergic activity is also associated with loss of the seizure protection seen following consumption of ketogenic diets. By contrast, knockout of the NE transporter (NET) gene, which elevates synaptic levels of norepinephrine, decreases seizure severity in mice fed normal diets. The purpose of this study was to compare the severity of maximal electroshock seizures in mice lacking the NET (NET KO) with that of wild type (WT) mice fed either a normal or a KD. In general, NET KO mice and mice fed a KD had a similar reduction in seizure severity, and the anticonvulsant effects of the genetic deletion of NET and the ketogenic diet were additive. These observations suggest that, while the noradrenergic system is required for the anti-seizure effects of the KD, additional mechanisms are involved.