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Abstract
A new generation of antiepileptic drugs has emerged; however, one-third of epilepsy patients do not properly respond to pharmacological treatments. The purpose of the present study was to investigate whether time-restricted feeding (TRF) has an anticonvulsant effect and whether this restrictive diet promotes changes in energy metabolism and epigenetic modifications in a pilocarpine-induced seizure model. To resolve our hypothesis, one group of rats had free access to food and water ad libitum (AL) and a second group underwent a TRF schedule. We used the lithium-pilocarpine model to induce status epilepticus (SE), and behavioral seizure monitoring was analyzed. Additionally, an electroencephalography (EEG) recording was performed to verify the effect of TRF on cortical electrical activity after a pilocarpine injection. For biochemical analysis, animals were sacrificed 24 h after SE and hippocampal homogenates were used to evaluate the proteins related to metabolism and chromatin structure. Our results showed that TRF had an anticonvulsant effect as measured by the prolonged latency of forelimb clonus seizure, a decrease in the seizure severity score and fewer animals reaching SE. Additionally, the power of the late phase EEG recordings in the AL group was significantly higher than the TRF group. Moreover, we found that TRF is capable of inducing alterations in signaling pathways that regulate energy metabolism, including an increase in the phosphorylation of AMP dependent kinase (AMPK) and a decrease in the phosphorylation of Akt kinase. Furthermore, we found that TRF was able to significantly increase the beta hydroxybutyrate (β-HB) concentration, an endogenous inhibitor of histone deacetylases (HDACs). Finally, we found a significant decrease in HDAC activity as well as an increase in acetylation on histone 3 (H3) in hippocampal homogenates from the TRF group. These findings suggest that alterations in energy metabolism and the increase in β-HB mediated by TRF may inhibit HDAC activity, thus increasing histone acetylation and producing changes in the chromatin structure, which likely facilitates the transcription of a subset of genes that confer anticonvulsant activity.
Highlights
Epilepsy is the third most common chronic brain disorder
Rats subjected to time-restricted feeding (TRF) consumed less food (5.8 gr) within the first 3 days compared to ad libitum (AL) animals (21.3 gr; Figure 1D, p < 0.001), and this result correlates with dramatic weight loss (Figure 1B)
To verify whether the TRF schedule could have an effect on animal growth, we calculated the ratio of the daily caloric intake consumed by each animal from the AL and TRF groups and divided this by the basal metabolic rate (BMR)
Summary
Epilepsy is the third most common chronic brain disorder. It affects 50 million people worldwide (Aroniadou-Anderjaska et al, 2008). A new generation of antiepileptic drugs has emerged, approximately 30% of epilepsy patients do not respond to classical pharmacological treatment (Löscher et al, 2013). For this reason, it is important to find new alternatives to complement pharmacological therapy in drug-resistant patients. A variety of reports suggest that some metabolismbased therapies, such as ketogenic diet (KD) or calorie restricted (CR) diets, have an anticonvulsant effect (Bough et al, 2003; Stafstrom and Rho, 2012). It has been suggested that the beneficial effect of these diets may be produced by means of a metabolic shift involving the activation of AMPactivated protein kinase (AMPK), inhibition of the mammalian target of rapamycin (mTOR) and overproduction of ketone bodies (Wong, 2010; McDaniel et al, 2011; Yuen and Sander, 2014)
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