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

Bryan V Phillips-Farfán,Karla G Carvajal Aguilera,Carlos Paz Tres,Verónica Custodio Ramírez,María Del Carmen Rubio Osornio

doi:10.3389/fncel.2015.00090

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.

Highlights

At first glance neurodegenerative diseases and epilepsy may seem to have little in common
We investigated if caloric restriction (CR) modified the expression of genes encoding for proteins participating in the mechanistic target of rapamycin (mTOR) cascade. This pathway is regulated by energy and insulin levels, which might be changed by CR; we studied whether CR altered the blood levels of glucose or βhydroxybutyrate (β-HB) or the plasma concentration of insulin
Bio-Indexes Body weights increased in both groups (Figure 1), but mild CR significantly reduced the weight gain of young animals [i.e., ad libitum (AL) vs. CR in days 6 vs. 7: F(1, 16) = 6.20, p < 0.05, t = 2.49; for all other comparisons see Supplementary Data]

Summary

Introduction

At first glance neurodegenerative diseases and epilepsy may seem to have little in common. Abnormal neural activity -the hallmark of epileptic disorders- might cause the synaptic and cognitive deficits observed in neurodegenerative diseases (Sanchez et al, 2012) Another unexpected commonality between neurodegenerative diseases and Abbreviations: CR, caloric restriction; mTOR, mechanistic target of rapamycin; β-HB, β-hydroxybutyrate; AMPK, adenosine monophosphate-activated protein kinase; PKB/Akt, protein kinase B; S6, ribosomal protein S6; S6K, ribosomal protein S6 kinase; TSC2, tuberous sclerosis 2; AL, ad libitum; AD, after-discharge; Cx, neocortex; Hp, hippocampus. Caloric restriction (CR) is a diet that has anti-epileptic and anti-epileptogenic effects in different animal models (Greene et al, 2001; Bough et al, 2003) Their mechanism of action is poorly understood; it has been reported that the ketogenic diet might inhibit the mTOR cascade (McDaniel et al, 2011). CR may inhibit the mTOR pathway in yeast, flies and nematodes (Kapahi et al, 2004; Kaeberlein et al, 2005; Walker et al, 2005)

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Results

Conclusion