The mammalian target of rapamycin (mTOR) pathway has been recently indicated as asuitable drug target for the prevention of epileptogenesis. The mTOR pathway isknown for its involvement in the control of the immune system. Sinceneuroinflammation is recognized as a major contributor to epileptogenesis, wewished to examine whether the neuroprotective effects of mTOR modulation couldinvolve a suppression of the neuroinflammatory process in epileptic brain. Wehave investigated the early molecular mechanisms involved in the effects ofintracerebral administration of the lipopolysaccharide (LPS) in the WAG/Rij ratmodel of absence epilepsy, in relation to seizure generation and depressive-like behavior; we also tested whether the effects of LPS could be modulated bytreatment with rapamycin (RAP), a specific mTOR inhibitor. We determined, inspecific rat brain areas, levels of p-mTOR/p-p70S6K and also p-AKT/p-AMPK asdownstream or upstream indicators of mTOR activity and tested the effects of LPS and RAP co-administration. Changes in the brain levels of pro-inflammatorycytokines IL-1β and TNF-α and their relative mRNA expression levels weremeasured, and the involvement of nuclear factor-κB (NF-κB) was also examined invitro. We confirmed that RAP inhibits the aggravation of absence seizures anddepressive-like/sickness behavior induced by LPS in the WAG/Rij rats through the activation of mTOR and show that this effect is correlated with the ability ofRAP to dampen and delay LPS increases in neuroinflammatory cytokines IL-1β andTNF-α, most likely through inhibition of the activation of NF-κB. Our resultssuggest that such a mechanism could contribute to the antiseizure,antiepileptogenic and behavioral effects of RAP and further highlight thepotential therapeutic usefulness of mTOR inhibition in the management of humanepilepsy and other neurological disorders. Furthermore, we show thatLPS-dependent neuroinflammatory effects are also mediated by a complex interplay between AKT, AMPK and mTOR with specificity to selective brain areas. Inconclusion, neuroinflammation appears to be a highly coordinated phenomenon,where timing of intervention may be carefully evaluated in order to identify the best suitable target.

The mammalian target of rapamycin (mTOR) pathway has been recently indicated as a suitable drug target for the prevention of epileptogenesis. The mTOR pathway is known for its involvement in the control of the immune system. Since neuroinflammation is recognized as a major contributor to epileptogenesis, we wished to examine whether the neuroprotective effects of mTOR modulation could involve a suppression of the neuroinflammatory process in epileptic brain. We have investigated the early molecular mechanisms involved in the effects of intracerebral administration of the lipopolysaccharide (LPS) in the WAG/Rij rat model of absence epilepsy, in relation to seizure generation and depressive-like behavior; we also tested whether the effects of LPS could be modulated by treatment with rapamycin (RAP), a specific mTOR inhibitor. We determined, in specific rat brain areas, levels of p-mTOR/p-p70S6K and also p-AKT/p-AMPK as downstream or upstream indicators of mTOR activity and tested the effects of LPS and RAP co-administration. Changes in the brain levels of pro-inflammatory cytokines IL-1β and TNF-α and their relative mRNA expression levels were measured, and the involvement of nuclear factor-κB (NF-κB) was also examined in vitro. We confirmed that RAP inhibits the aggravation of absence seizures and depressive-like/sickness behavior induced by LPS in the WAG/Rij rats through the activation of mTOR and show that this effect is correlated with the ability of RAP to dampen and delay LPS increases in neuroinflammatory cytokines IL-1β and TNF-α, most likely through inhibition of the activation of NF-κB. Our results suggest that such a mechanism could contribute to the antiseizure, antiepileptogenic and behavioral effects of RAP and further highlight the potential therapeutic usefulness of mTOR inhibition in the management of human epilepsy and other neurological disorders. Furthermore, we show that LPS-dependent neuroinflammatory effects are also mediated by a complex interplay between AKT, AMPK and mTOR with specificity to selective brain areas. In conclusion, neuroinflammation appears to be a highly coordinated phenomenon, where timing of intervention may be carefully evaluated in order to identify the best suitable target.

Early molecular and behavioral response to lipopolysaccharide in the WAG/Rij rat model of absence epilepsy and depressive-like behavior, involves interplay between AMPK, AKT/mTOR pathways and neuroinflammatory cytokine release

Russo E
;
Andreozzi F;Iuliano R;Dattilo V;Fiume G;Mimmi S;Perrotti N;Citraro R;Sesti G;De Sarro G
2014-01-01

Abstract

The mammalian target of rapamycin (mTOR) pathway has been recently indicated as asuitable drug target for the prevention of epileptogenesis. The mTOR pathway isknown for its involvement in the control of the immune system. Sinceneuroinflammation is recognized as a major contributor to epileptogenesis, wewished to examine whether the neuroprotective effects of mTOR modulation couldinvolve a suppression of the neuroinflammatory process in epileptic brain. Wehave investigated the early molecular mechanisms involved in the effects ofintracerebral administration of the lipopolysaccharide (LPS) in the WAG/Rij ratmodel of absence epilepsy, in relation to seizure generation and depressive-like behavior; we also tested whether the effects of LPS could be modulated bytreatment with rapamycin (RAP), a specific mTOR inhibitor. We determined, inspecific rat brain areas, levels of p-mTOR/p-p70S6K and also p-AKT/p-AMPK asdownstream or upstream indicators of mTOR activity and tested the effects of LPS and RAP co-administration. Changes in the brain levels of pro-inflammatorycytokines IL-1β and TNF-α and their relative mRNA expression levels weremeasured, and the involvement of nuclear factor-κB (NF-κB) was also examined invitro. We confirmed that RAP inhibits the aggravation of absence seizures anddepressive-like/sickness behavior induced by LPS in the WAG/Rij rats through the activation of mTOR and show that this effect is correlated with the ability ofRAP to dampen and delay LPS increases in neuroinflammatory cytokines IL-1β andTNF-α, most likely through inhibition of the activation of NF-κB. Our resultssuggest that such a mechanism could contribute to the antiseizure,antiepileptogenic and behavioral effects of RAP and further highlight thepotential therapeutic usefulness of mTOR inhibition in the management of humanepilepsy and other neurological disorders. Furthermore, we show thatLPS-dependent neuroinflammatory effects are also mediated by a complex interplay between AKT, AMPK and mTOR with specificity to selective brain areas. Inconclusion, neuroinflammation appears to be a highly coordinated phenomenon,where timing of intervention may be carefully evaluated in order to identify the best suitable target.
2014
The mammalian target of rapamycin (mTOR) pathway has been recently indicated as a suitable drug target for the prevention of epileptogenesis. The mTOR pathway is known for its involvement in the control of the immune system. Since neuroinflammation is recognized as a major contributor to epileptogenesis, we wished to examine whether the neuroprotective effects of mTOR modulation could involve a suppression of the neuroinflammatory process in epileptic brain. We have investigated the early molecular mechanisms involved in the effects of intracerebral administration of the lipopolysaccharide (LPS) in the WAG/Rij rat model of absence epilepsy, in relation to seizure generation and depressive-like behavior; we also tested whether the effects of LPS could be modulated by treatment with rapamycin (RAP), a specific mTOR inhibitor. We determined, in specific rat brain areas, levels of p-mTOR/p-p70S6K and also p-AKT/p-AMPK as downstream or upstream indicators of mTOR activity and tested the effects of LPS and RAP co-administration. Changes in the brain levels of pro-inflammatory cytokines IL-1β and TNF-α and their relative mRNA expression levels were measured, and the involvement of nuclear factor-κB (NF-κB) was also examined in vitro. We confirmed that RAP inhibits the aggravation of absence seizures and depressive-like/sickness behavior induced by LPS in the WAG/Rij rats through the activation of mTOR and show that this effect is correlated with the ability of RAP to dampen and delay LPS increases in neuroinflammatory cytokines IL-1β and TNF-α, most likely through inhibition of the activation of NF-κB. Our results suggest that such a mechanism could contribute to the antiseizure, antiepileptogenic and behavioral effects of RAP and further highlight the potential therapeutic usefulness of mTOR inhibition in the management of human epilepsy and other neurological disorders. Furthermore, we show that LPS-dependent neuroinflammatory effects are also mediated by a complex interplay between AKT, AMPK and mTOR with specificity to selective brain areas. In conclusion, neuroinflammation appears to be a highly coordinated phenomenon, where timing of intervention may be carefully evaluated in order to identify the best suitable target.
Lipopolysaccharide (LPS); Neuroinflammation; Epileptogenesis; Absence epilepsy; WAG/Rij rats; mTOR; AKT; AMPK; Cytokines; NF-kB; Rapamycin
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.12317/8550
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