Abstract
Among non-pharmacological treatments, the ketogenic diet (KD) has the strongest demonstrated evidence of clinical success in drug resistant epilepsy. In an attempt to model the anticonvulsant effects of the KD pre-clinically, the present study assessed the effects of the KD against electroshock-induced convulsions in mice. After confirming that exposure to the KD for 2 weeks resulted in stable ketosis and hypoglycemia, mice were exposed to electroshocks of various intensities to establish general seizure susceptibility. When compared to mice fed the standard rodent chow diet (SRCD), we found that mice fed the KD were more sensitive to electroconvulsions as reflected by a significant decrease in seizure threshold (3.86 mA in mice on the KD vs 7.29 mA in mice on the SRCD; P < 0.05) in the maximal electroshock seizure threshold (MEST) test. To examine if this increased seizure sensitivity to electroconvulsions produced by the KD would affect anticonvulsant effects of antiepileptic drugs (AEDs), anticonvulsant potencies of carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and valproate (VPA) against maximal electroshock (MES)-induced convulsions were compared in mice fed the KD and SRCD. We found that potencies of all AEDs studied were decreased in mice fed the KD in comparison to those on the SRCD, with decreases in the anticonvulsant potencies ranging from 1.4 fold (PB) to 1.7 fold (PHT). Finally, the lack of differences in brain exposures of the AEDs studied in mice fed the KD and SRCD ruled out a pharmacokinetic nature of the observed findings. Taken together, exposure to the KD in the present study had an overall pro-convulsant effect. Since electroconvulsions require large metabolic reserves to support their rapid spread throughout the brain and consequent generalized tonic-clonic convulsions, this effect may be explained by a high energy state produced by the KD in regards to increased energy storage and utilization.
Highlights
Drug resistant epilepsy continues to be a significant unmet medical need despite the availability of more than 25 approvedMetab Brain Dis (2017) 32:351–358 antiepileptic drugs (AEDs) (Loscher et al 2013)
We found that potencies of all AEDs studied were decreased in mice fed the ketogenic diet (KD) in comparison to those on the standard rodent chow diet (SRCD), with decreases in the anticonvulsant potencies ranging from 1.4 fold (PB) to 1.7 fold (PHT)
Effect of the KD on the anticonvulsant action of AEDs in the maximal electroshock (MES) test The anticonvulsant dose-effect function and resulting anticonvulsant ED50 values for each AEDs tested in the MES test are showed in Fig. 1 and Table 1, respectively
Summary
Drug resistant epilepsy continues to be a significant unmet medical need despite the availability of more than 25 approvedMetab Brain Dis (2017) 32:351–358 antiepileptic drugs (AEDs) (Loscher et al 2013). The dietary approach by substituting the regular diet with the ketogenic diets (KDs) has the strongest evidence so far of clinical success in drug resistant epilepsy (Li et al 2013; Reid et al 2014). This has fueled interest in understanding mechanisms responsible for KD’s anticonvulsant and perhaps disease-modifying (i.e., antiepileptogenic) properties (Allen et al 2014; Danial et al 2013; Gasior et al 2006; Hartman et al 2007; Masino and Rho 2012). Those studies revealed mixed results (i.e. ranging from no effect to anticonvulsant or proconvulsant) on the effects of the KDs on seizures in the MES or MEST seizure tests, which is the case when tested and compared across other experimental settings (Hartman et al 2007; Samala et al 2008; Masino and Rho 2012)
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