Caloric restriction protects against electrical kindling of the amygdala by inhibiting the mTOR signaling pathway

Abstract

Caloric restriction (CR) has been shown to possess antiepileptic properties; however its mechanism of action is poorly understood. CR might inhibit the activity of the mammalian or mechanistic target of rapamycin (mTOR) signaling cascade, which seems to participate crucially in the generation of epilepsy. Thus, we investigated the effect of CR on the mTOR pathway and whether CR modified epilepsy generation due to electrical amygdala kindling. The former was studied by analyzing the phosphorylation of adenosine monophosphate-activated protein kinase, protein kinase B and the ribosomal protein S6. The mTOR cascade is regulated by energy and by insulin levels, both of which may be changed by CR; thus we investigated if CR altered the levels of energy substrates in the blood or the level of insulin in plasma. Finally, we studied if CR modified the expression of genes that encode proteins participating in the mTOR pathway. CR increased the after-discharge threshold and tended to reduce the after-discharge duration, indicating an anti-convulsive action. CR diminished the phosphorylation of protein kinase B and ribosomal protein S6, suggesting an inhibition of the mTOR cascade. However, CR did not change glucose, β-hydroxybutyrate or insulin levels; thus the effects of CR were independent from them. Interestingly, CR also did not modify the expression of any investigated gene. The results suggest that the anti-epileptic effect of CR may be partly due to inhibition of the mTOR pathway.

Anticonvulsant Effect of Time-Restricted Feeding in a Pilocarpine-Induced Seizure Model: Metabolic and Epigenetic Implications

“…Nevertheless, food intake and body weight were lower compared to AL-fed rats. Regarding blood glucose levels, there were no significant changes between the AL and TRF groups, which showed similar results to other dietary models (Phillips-Farfán et al, 2015 ). However, in glucose tolerance experiments, TRF-subjected animals seemed to better metabolize glucose than AL-fed animals at 15 and 20 days, suggesting that glucose metabolism in TRF animals is more efficient or is not altered as in AL-fed animals.…”

“…One possible explanation for the anticonvulsant effect of TRF could be through the activation of AMPK, which regulates mTOR (Laplante and Sabatini, 2012 ), a protein kinase that is closely related to the process of epileptogenesis (Zeng et al, 2009 ; Nguyen et al, 2015 ). In accordance, Phillips-Farfán et al ( 2015 ) recently showed an increase in AMPK phosphorylation and a decrease in phospho-PKB (p-Akt), together with a decrease in phospho-S6 ribosomal protein in hippocampal homogenates in an electrical kindling model. Interestingly, similar effects on mTOR kinase downstream targets in the hippocampus were found using a KD in a kainic acid-induced seizure model (McDaniel et al, 2011 ).…”

“…Most importantly, at day 5, animals that followed the TRF schedule had a reduction of 10% of their body weight; however, this group tended to recover their weight at day 15, confirming that this model induces body weight loss, as has been previously described (Amigo and Kowaltowski, 2014 ). Interestingly, a similar result in body weight loss was observed in young rats subjected to a 15% of CR schedule for 30 days (Phillips-Farfán et al, 2015 ), suggesting that both diets may have similar effects. Such a drastic weight reduction can be correlated with a decrease in food intake, as observed in the TRF model during the early days of the study.…”

“…To date, there is no evidence showing that TRF might have an anticonvulsant effect; however, it has been shown that CR diminishes neuronal excitability and increases the after-discharged threshold in an electrical stimulation seizure model (Bough et al, 2003 ; Phillips-Farfán et al, 2015 ). In accordance with this assumption, our results suggest that TRF may inhibit seizure susceptibility and induce similar anticonvulsant effects in the pilocarpine-induced SE.…”

Caloric Restriction and Ketogenic Diet Therapy for Epilepsy: A Molecular Approach Involving Wnt Pathway and KATP Channels

“…CR reduces caloric energy consumption without causing eating disorders or any specific nutrient deficiency (80). In addition to improving health status, CR has anticonvulsant effects in murine and other epilepsy models (81,82). Moreover, it is proposed that the anti-epileptic action of CR may require a reduction in glucose or insulin concentrations and an increase in the β-hydroxybutyrate (β-HB) ketone body (83), along with increased fatty acid oxidation and reduced lipid accumulation in some tissues, as CR has been strongly related with improving insulin sensitivity and increasing adiponectin levels (84).…”