Ketogenic diet treatment abolishes seizure periodicity and improves diurnal rhythmicity in epileptic Kcna1‐null mice

Abstract

Summary Introduction Seizures are known to perturb circadian rhythms in humans as well as in animal models of epilepsy. However, it is unknown whether treatment of the underlying epilepsy restores normal biological rhythms. We asked whether: (1) seizure activity is characterized by diurnal rhythmicity; (2) chronically epileptic mice exhibit impaired activity-rest rhythms; and (3) treatment with the anticonvulsant ketogenic diet (KD) improves such perturbations. Methods Chronically epileptic Kcna1-null mice were fed either a standard diet or KD for 4 wks and subjected to continuous video-EEG and actigraphy monitoring for 3–5 days to assess seizure activity and rest-activity cycles. Results Seizure activity in Kcna1-null mice demonstrated diurnal rhythmicity, peaking at zeitgeber (ZT) 2.30±1.52. Activity-rest rhythms of epileptic mice were significantly disrupted. Whereas locomotor activity for wild-type mice peaked at ZT15.45±0.28 (ZT14:26–ZT16:51), peak activity of epileptic mice was more unpredictable, occurring over a 12.4hr range (ZT06:33–ZT18:57). In 6 of 9 epileptic mice, peak activity was delayed to ZT17.42±0.38, while peak activity was advanced to ZT10.00±1.26 in the remaining mice. Treatment with the KD abolished seizure periodicity and restored the activity-rest rhythm to values resembling those of wild-type mice (i.e. activity peaking at ZT16.73±0.67). Conclusions Kcna1-null mice experience seizures with 24-hr periodicity and impaired circadian behavior. KD reduces the number and periodicity of seizures and restores normal behavioral rhythms, suggesting that this non-pharmacological therapy may benefit biological rhythm disturbances in epileptic patients.

Ketone bodies mediate antiseizure effects through mitochondrial permeability transition

“…These seizures possess many of the characteristics of limbic system seizures in other rodent models (e.g., rearing, forelimb clonus) as they evolve into whole-body tonic-clonic activity, suggesting that the hippocampus may play an important role in their pathogenesis. 16,23 Figure 1A illustrates typical EEG findings in wild-type mice, as well as interictal and ictal EEG changes seen in Kcna1 -null mutants. Consistent with our earlier observations, 23 we found that a widely employed experimental KD significantly reduced SRS in Kcna1 -null mice compared to SD-fed controls during active treatment (Fig 1B), and was accompanied by elevations in plasma BHB and decreases in blood glucose levels (Fig 2A, 2B).…”

“…16,23 Figure 1A illustrates typical EEG findings in wild-type mice, as well as interictal and ictal EEG changes seen in Kcna1 -null mutants. Consistent with our earlier observations, 23 we found that a widely employed experimental KD significantly reduced SRS in Kcna1 -null mice compared to SD-fed controls during active treatment (Fig 1B), and was accompanied by elevations in plasma BHB and decreases in blood glucose levels (Fig 2A, 2B). We next asked whether in vivo KB administration alone would block SRS.…”

Regulation of brain PPARgamma2 contributes to ketogenic diet anti-seizure efficacy

“…One ground (1.5mm anterior lamba, 1.5mm lateral) and two subdural (1mm posterior Bregma, 1.5mm bilateral) iEEG electrodes were implanted, secured and attached to a headmount. Following a 5–6 day recovery, seizures were monitored for forty-eight hours using a continuous infrared video surveillance system time-synced to an EEG recording system (Pinnacle Technology, Inc., Lawrence, KS, U.S.A) as we have described (Roundtree et al, 2016; Simeone et al, 2014a; Fenoglio-Simeone et al, 2009a,b). EEG recordings were acquired with a 250 Hz sampling rate and band-pass filtered between 0.5 and 40 Hz.…”

“…Subsequently, EEG seizures were confirmed using Sirenia software (Pinnacle Technology, Inc.) that time-synced EEG and video recordings and behavioral manifestations were manually verified by 2 blinded investigators. Incidence and severity of each seizure was scored for the first 15 min of each hour during the time period of highest seizure occurrence for Kv1.1KO mice (00:00–08:00) (Simeone et al, 2014a; Fenoglio-Simeone et al, 2009b). Seizure severity was scored using a modified Racine scale: 0-normal; 1-myoclonic jerk; 2-side-to-side head movement; 3-forelimb/hindlimb clonus, tail extension, a single rearing event; 4-continuous rearing and falling; 5-severe tonic-clonic seizures.…”

The Ketogenic Diet Modifies Social and Metabolic Alterations Identified in the Prenatal Valproic Acid Model of Autism Spectrum Disorder

“…The rats were born and reared in a quiet, temperature-controlled room and entrained to a 12-hour light-dark cycle. After weaning at postnatal day 21 (PD21), the rats were placed on either SD or KD (6:1 fat to carbohydrates plus proteins; Bio-Serv F3666, Frenchtown, N.J., USA) for 10-14 days [37]. …”