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Finding a better drug for epilepsy: The mTOR pathway as an antiepileptogenic target

Saul R. Korey Department of Neurology, Dominick P. Purpura Department of Neuroscience, Laboratory of Developmental Epilepsy, Montefiore/Einstein Epilepsy Management Center, Albert Einstein College of Medicine, Bronx, New York, USA.
Epilepsia (Impact Factor: 4.57). 05/2012; 53(7):1119-30. DOI: 10.1111/j.1528-1167.2012.03506.x
Source: PubMed

ABSTRACT

The mammalian target of rapamycin (mTOR) signaling pathway regulates cell growth, differentiation, proliferation, and metabolism. Loss-of-function mutations in upstream regulators of mTOR have been highly associated with dysplasias, epilepsy, and neurodevelopmental disorders. These include tuberous sclerosis, which is due to mutations in TSC1 or TSC2 genes; mutations in phosphatase and tensin homolog (PTEN) as in Cowden syndrome, polyhydramnios, megalencephaly, symptomatic epilepsy syndrome (PMSE) due to mutations in the STE20-related kinase adaptor alpha (STRADalpha); and neurofibromatosis type 1 attributed to neurofibromin 1 mutations. Inhibition of the mTOR pathway with rapamycin may prevent epilepsy and improve the underlying pathology in mouse models with disrupted mTOR signaling, due to PTEN or TSC mutations. However the timing and duration of its administration appear critical in defining the seizure and pathology-related outcomes. Rapamycin application in human cortical slices from patients with cortical dysplasias reduces the 4-aminopyridine-induced oscillations. In the multiple-hit model of infantile spasms, pulse high-dose rapamycin administration can reduce the cortical overactivation of the mTOR pathway, suppresses spasms, and has disease-modifying effects by partially improving cognitive deficits. In post-status epilepticus models of temporal lobe epilepsy, rapamycin may ameliorate the development of epilepsy-related pathology and reduce the expression of spontaneous seizures, but its effects depend on the timing and duration of administration, and possibly the model used. The observed recurrence of seizures and epilepsy-related pathology after rapamycin discontinuation suggests the need for continuous administration to maintain the benefit. However, the use of pulse administration protocols may be useful in certain age-specific epilepsy syndromes, like infantile spasms, whereas repetitive-pulse rapamycin protocols may suffice to sustain a long-term benefit in genetic disorders of the mTOR pathway. In summary, mTOR dysregulation has been implicated in several genetic and acquired forms of epileptogenesis. The use of mTOR inhibitors can reverse some of these epileptogenic processes, although their effects depend upon the timing and dose of administration as well as the model used.

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    • "In some rats epilepsy does not even develop (Van Vliet et al., 2012). Therefore, mTOR inhibitors are suggested as new therapeutic strategy for people with epilepsy (Galanopoulou et al., 2012; Curatolo and Moavero, 2013; Wong, 2013). In a recent prospective, multicenter, open-label, phase I/II clinical trial, the mTOR inhibitor everolimus improved seizure control in the majority of people with Tuberous Sclerosis Complex with medically refractory epilepsy (Krueger et al., 2013). "

    Full-text · Dataset · Aug 2014
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    • "In some rats epilepsy does not even develop (Van Vliet et al., 2012). Therefore, mTOR inhibitors are suggested as new therapeutic strategy for people with epilepsy (Galanopoulou et al., 2012; Curatolo and Moavero, 2013; Wong, 2013). In a recent prospective, multicenter, open-label, phase I/II clinical trial, the mTOR inhibitor everolimus improved seizure control in the majority of people with Tuberous Sclerosis Complex with medically refractory epilepsy (Krueger et al., 2013). "
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    • "The most well studied neuroinflammatory mediators in epilepsy and depression are represented by the so-called acute phase response induction cytokines, particularly interleukin-1b (IL-1b) and tumor necrosis factor-a (TNF-a) (Lang and Borgwardt, 2013; Vezzani et al., 2011). Recently, the mammalian target of rapamycin (mTOR) signaling pathway has been indicated as particularly relevant to epilepsy and epileptogenic processes (Vezzani et al., 2013; Wong, 2013) in view of its activation during the epileptogenic phase of several animal epilepsy models and the ability of its specific inhibitor, rapamycin (RAP), to prevent the development of spontaneous seizures (both convulsive and non-convulsive) (Galanopoulou et al., 2012; Maiese et al., 2013; Russo et al., 2012a). Despite the fact that the exact antiepileptogenic mechanism of RAP is unclear, some more recent studies have indicated that a modulation of the immune system might be crucially involved (Macias et al., 2013; Russo et al., 2013c; van Vliet et al., 2012; Wang et al., 2013). "
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    ABSTRACT: 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.
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