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

Phillips-Farfán BV, Rubio Osornio Mdel C, Custodio Ramírez V, Paz Tres C, Carvajal Aguilera KG - Front Cell Neurosci (2015)

Bottom Line: CR increased the after-discharge threshold and tended to reduce the after-discharge duration, indicating an anti-convulsive action.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de Nutrición Experimental, Instituto Nacional de Pediatría México City, México.

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.

No MeSH data available.


Related in: MedlinePlus

Phosphorylation of proteins participating in the mechanistic target of rapamycin signaling pathway in the neocortex (Cx) and hippocampus (Hp) of animals allowed to feed ad libitum (AL) or subjected to a 15% caloric restriction (CR). (A) Expression of phospho-AMPK against total AMPK. (B) Proportion of phospho-PKB vs. total PKB. (C) Phospho-S6 to total S6 ratio. *p ≤ 0.05, **p ≤ 0.01, AL vs. CR.
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Figure 5: Phosphorylation of proteins participating in the mechanistic target of rapamycin signaling pathway in the neocortex (Cx) and hippocampus (Hp) of animals allowed to feed ad libitum (AL) or subjected to a 15% caloric restriction (CR). (A) Expression of phospho-AMPK against total AMPK. (B) Proportion of phospho-PKB vs. total PKB. (C) Phospho-S6 to total S6 ratio. *p ≤ 0.05, **p ≤ 0.01, AL vs. CR.

Mentions: CR tended to augment AMPK phosphorylation (Figures 4, 5) in the Cx [t(1, 18) = −1.47, p = 0.16] and significantly increased AMPK phosphorylation in the Hp [t(1, 18) = −2.44, p < 0.05]. CR significantly reduced PKB/Akt and S6 phosphorylation in the Cx [PKB: t(1, 18) = 3.03, p < 0.01 and S6: t(1, 18) = 2.13, p < 0.05] and Hp [PKB: t(1, 18) = 3.13, p < 0.01 and S6: t(1, 18) = 2.39, p < 0.05], suggesting that CR inhibited the mTOR cascade. Finally, CR did not significantly change the expression level of the studied genes [Figure 6; AMPKα1: Cx: t(1, 18) = 0.40, p = 0.70, Hp: t(1, 18) = 0.62, p = 0.54; AMPKα2: Cx: t(1, 18) = 1.37, p = 0.19, Hp: t(1, 18) = 0.57, p = 0.58; mTOR: Cx: t(1, 18) = −1.09, p = 0.29, Hp: t(1, 18) = −1.71, p = 0.10; S6K: Cx: t(1, 18) = 1.78, p = 0.09, Hp: t(1, 18) = 0.08, p = 0.94; TSC1: Cx: t(1, 18) = 1.74, p = 0.10, Hp: t(1, 18) = −1.33, p = 0.20; TSC2: Cx: t(1, 18) = 0.27, p = 0.79, Hp: t(1, 18) = 0.58, p = 0.57].


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

Phillips-Farfán BV, Rubio Osornio Mdel C, Custodio Ramírez V, Paz Tres C, Carvajal Aguilera KG - Front Cell Neurosci (2015)

Phosphorylation of proteins participating in the mechanistic target of rapamycin signaling pathway in the neocortex (Cx) and hippocampus (Hp) of animals allowed to feed ad libitum (AL) or subjected to a 15% caloric restriction (CR). (A) Expression of phospho-AMPK against total AMPK. (B) Proportion of phospho-PKB vs. total PKB. (C) Phospho-S6 to total S6 ratio. *p ≤ 0.05, **p ≤ 0.01, AL vs. CR.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4356078&req=5

Figure 5: Phosphorylation of proteins participating in the mechanistic target of rapamycin signaling pathway in the neocortex (Cx) and hippocampus (Hp) of animals allowed to feed ad libitum (AL) or subjected to a 15% caloric restriction (CR). (A) Expression of phospho-AMPK against total AMPK. (B) Proportion of phospho-PKB vs. total PKB. (C) Phospho-S6 to total S6 ratio. *p ≤ 0.05, **p ≤ 0.01, AL vs. CR.
Mentions: CR tended to augment AMPK phosphorylation (Figures 4, 5) in the Cx [t(1, 18) = −1.47, p = 0.16] and significantly increased AMPK phosphorylation in the Hp [t(1, 18) = −2.44, p < 0.05]. CR significantly reduced PKB/Akt and S6 phosphorylation in the Cx [PKB: t(1, 18) = 3.03, p < 0.01 and S6: t(1, 18) = 2.13, p < 0.05] and Hp [PKB: t(1, 18) = 3.13, p < 0.01 and S6: t(1, 18) = 2.39, p < 0.05], suggesting that CR inhibited the mTOR cascade. Finally, CR did not significantly change the expression level of the studied genes [Figure 6; AMPKα1: Cx: t(1, 18) = 0.40, p = 0.70, Hp: t(1, 18) = 0.62, p = 0.54; AMPKα2: Cx: t(1, 18) = 1.37, p = 0.19, Hp: t(1, 18) = 0.57, p = 0.58; mTOR: Cx: t(1, 18) = −1.09, p = 0.29, Hp: t(1, 18) = −1.71, p = 0.10; S6K: Cx: t(1, 18) = 1.78, p = 0.09, Hp: t(1, 18) = 0.08, p = 0.94; TSC1: Cx: t(1, 18) = 1.74, p = 0.10, Hp: t(1, 18) = −1.33, p = 0.20; TSC2: Cx: t(1, 18) = 0.27, p = 0.79, Hp: t(1, 18) = 0.58, p = 0.57].

Bottom Line: CR increased the after-discharge threshold and tended to reduce the after-discharge duration, indicating an anti-convulsive action.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de Nutrición Experimental, Instituto Nacional de Pediatría México City, México.

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.

No MeSH data available.


Related in: MedlinePlus