mTOR inhibition modulates epileptogenesis, seizures and depressive behavior in a genetic rat model of absence epilepsy

Russo, Emilio; Citraro, Rita; Donato, Giuseppe; Camastra, Caterina; Iuliano, Rodolfo; Cuzzocrea, Salvatore; Constanti, Andrew; Sarro, Giovambattista De

doi:10.1016/j.neuropharm.2012.09.019

Cited by 107 publications

(116 citation statements)

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“…Recently, the involvement of the mTOR pathway in absence seizures of WAG/Rij rats was demonstrated; chronic oral treatment with rapamycin (see Section 4), started prior to the onset of seizures, reduced the subsequent development of SWDs in adult WAG/Rij rats, thus displaying antiepileptogenic properties (Russo et al, 2013b). These effects were linked to the ability of mTOR to modulate neuroinflammation, which was studied in this strain following the pharmacological interaction between rapamycin and LPS (see below); furthermore, it has been demonstrated that WAG/Rij rats in comparison to Wistar rats, have higher levels of total mTOR in several brain areas, including the cortex, hippocampus and thalamus (Russo et al, 2014b).…”

Section: Glia Neuroinflammation and The Mtor Pathwaymentioning

confidence: 99%

Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development

Russo

Citraro

Constanti³

et al. 2016

Neuroscience & Biobehavioral Reviews

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128

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Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development.Neuroscience and Biobehavioral Reviews http://dx.doi.org/10. 1016/j.neubiorev.2016.09.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractThe WAG/Rij rat model has recently gathered attention as a suitable animal model of absence epileptogenesis. This latter term has a broad definition encompassing any possible cause that determines the development of spontaneous seizures; however, most of, if not all, preclinical knowledge on epileptogenesis is confined to the study of post-brain insult models such as traumatic brain injury or post-status epilepticus models. WAG/Rij rats, but also synapsin 2 knockout, Kv7 current-deficient mice represent the first examples of genetic models where an efficacious antiepileptogenic treatment (ethosuximide) was started before seizure onset. In this review, we have critically reconsidered all articles published regarding WAG/Rij rats, from the perspective that the period before SWD onset is considered as the latent period. In our new theory on seizure development, it is proposed that genes might be considered as the initial "insult" responsible for all plastic changes underpinning the development of spontaneous seizures. According to this idea, in WAG/Rij rats, genetic predisposition would lead to the development of abnormal bilateral cortical epileptic foci, which would then nongenetically stimulate the rest of the brain to rearrange networks in order to phenotypically develop seizures similarly to what happens during electrical kindling.

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Section: Glia Neuroinflammation and The Mtor Pathwaymentioning

confidence: 99%

Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development

Russo

Citraro

Constanti³

et al. 2016

Neuroscience & Biobehavioral Reviews

Self Cite

128

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“…This hypothesis is also supported by the fact that a sub-chronic treatment with fingolimod neither reduced mTOR pathway activation nor absence seizures in adult WAG/Rij rats. Furthermore, it was previously demonstrated that the mTOR inhibitor rapamycin has both antiepileptogenic effects (about 50% seizure development decrease vs 30% obtained with fingolimod) and some, albeit limited, anti-absence effects with longlasting antiepileptogenic effects [29,31]. Of note, we found an age-dependent increase in the phosphorylation of p-AKT in older control rats [68]; however, the significance of this result still remains controversial [69].…”

Section: Discussionmentioning

confidence: 59%

“…However, these effects, as reported for the majority of the drugs tested in this model so far, were transitory, since 5 months after treatment discontinuation, both absence seizures and depressive-like behavior (which usually accompanies seizure development in WAG/Rij rats), returned to control level [26,27,31]. Furthermore, comparing fingolimod effects in WAG/Rij rats of 6 months of age (i.e.…”

Section: Discussionmentioning

confidence: 61%

“…The forced swimming test (FST), despite some limitations [50], is currently used for the experimental study of depressive-like behavior in animals; we used an FST protocol previously standardized in our laboratories [31,48]. Briefly, rats were placed individually for 6 min into a glass cylinder (height 47 cm, diameter 38 cm) filled with 38 cm of water, maintained at 23-25°C.…”

Section: Forced Swimming Testmentioning

confidence: 99%

“…Despite in this latter model neuroinflamamtion does not seem to play a major role [28]; it has been demonstrated that drugs (e.g. etoricoxib, indomethacin and rapamycin) acting on inflammation can both reduce absence seizures and their development and accordingly, increasing neuroinflammation increases absence seizures 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 5 [11,[29][30][31]. The role of inflammatory cytokines have been previously studied by Van Luijtelaar et al [28], IL-1beta and TNF-alpha administration can both increase absence seizures in this model while their levels were found to be altered in the blood and/or the brain of WAG/Rij rats at some ages with no clear correlation with SWDs development concluding therefore that a possible modulatory effect of neuroinflammation is plausible but TNF-alpha might not have necessarily a negative impact as also suggested by some other previous articles in other models [32].…”

Section: Introductionmentioning

confidence: 99%

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Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model

et al. 2017

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One of the major challenges in the epilepsy field is identifying disease-modifying drugs in order to prevent or delay spontaneous recurrent seizure onset or to cure already established epilepsy. It has been recently reported that fingolimod, currently approved for the treatment of relapsing-remitting multiple sclerosis, has demonstrated antiepileptogenic effects in two different preclinical models of acquired epilepsy. However, to date, no data exist regarding the role of fingolimod against genetic epilepsy. Therefore, we have addressed this issue by studying the effects of fingolimod in WAG/Rij rats, a well-established genetic model of absence epilepsy, epileptogenesis, and neuropsychiatric comorbidity. Our results have demonstrated that an early-long term treatment with fingolimod (1 mg/Kg/day), started before absence seizure onset, has both antiepileptogenic and antidepressant-like effects in the WAG/Rij rats. However, these effects were transitory, since 5 months after treatment discontinuation, both absence seizure and depressive like-behavior returned to control level.Furthermore, a temporary reduction of mTOR signaling pathway activity, indicated by reduced p-mTOR and p-p70S6k levels and by an increased p-AKT in WAG/Rij rats of 6 months of age accompanied the transitory antiepileptogenic fingolimod effects. Surprisingly, fingolimod has demonstrated longer-lasting positive effects on cognitive decline in this strain. This effect was accompanied by an increased acetylation of Lysine 8 of histone H4 (both 6 and 10 months of age). In conclusion, our results support the antiepileptogenic effects fingolimod. However, these antiepileptogenic effects were transitory. Moreover, fingolimod might also have a positive impact on animal behavior and particularly in protecting the development of memory decline.

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Everolimus treatment of refractory epilepsy in tuberous sclerosis complex

Krueger

Wilfong

Holland‐Bouley

et al. 2013

Annals of Neurology

352

253

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Objective: Epilepsy is a major manifestation of tuberous sclerosis complex (TSC). Everolimus is an mammalian target of rapamycin complex 1 inhibitor with demonstrated benefit in several aspects of TSC. We report the first prospective human clinical trial to directly assess whether everolimus will also benefit epilepsy in TSC patients. Methods: The effect of everolimus on seizure control was assessed using a prospective, multicenter, open-label, phase I/II clinical trial. Patients 2 years of age with confirmed diagnosis of TSC and medically refractory epilepsy were treated for a total of 12 weeks. The primary endpoint was percentage of patients with a 50% reduction in seizure frequency over a 4-week period before and after treatment. Secondary endpoints assessed impact on electroencephalography (EEG), behavior, and quality of life. Results: Twenty-three patients were enrolled, and 20 patients were treated with everolimus. Seizure frequency was reduced by 50% in 12 of 20 subjects. Overall, seizures were reduced in 17 of the 20 by a median reduction of 73% (p < 0.001). Seizure frequency was also reduced during 23-hour EEG monitoring (p 5 0.007). Significant reductions in seizure duration and improvement in parent-reported behavior and quality of life were also observed. There were 83 reported adverse events that were thought to be treatment-related, all of which were mild or moderate in severity. Interpretation: Seizure control improved in the majority of TSC patients with medically refractory epilepsy following treatment with everolimus. Everolimus demonstrated additional benefits on behavior and quality of life. Treatment was safe and well tolerated. Everolimus may be a therapeutic option for refractory epilepsy in this population.

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mTOR inhibition modulates epileptogenesis, seizures and depressive behavior in a genetic rat model of absence epilepsy

Cited by 107 publications

References 106 publications

Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development

Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development

Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model

Everolimus treatment of refractory epilepsy in tuberous sclerosis complex

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