Rapamycin has a beneficial effect on controlling epilepsy in children with tuberous sclerosis complex: results of 7 children from a cohort of 86

Canpolat, Mehmet; Per, Hüseyin; Gümüş, Hakan; Yıkılmaz, Ali; Ünal, Ekrem; Patıroğlu, Türkan; Çınar, Salih Levent; Kurtsoy, Ali; Kumandaş, Sefer

doi:10.1007/s00381-013-2185-6

Cited by 38 publications

(24 citation statements)

References 70 publications

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“…Even if we used the lower rapamycin dose, the growth-retarding effects were evident. In more severe epilepsies such as those associated with TSC, rapamycin can still be a useful drug, since its beneficial effects may outweigh the negative side effects; clinical trials appear successful [37][38][39] and recently, it was found that intermittent dosing of rapamycin is effective, while limiting the side effects in a mouse model of TSC. 23 Recently we also reported a significant reduction in brain growth after 6-week rapamycin treatment in KA-treated rats.…”

Section: Discussionmentioning

confidence: 99%

Effects of rapamycin and curcumin treatment on the development of epilepsy after electrically induced status epilepticus in rats

et al. 2016

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SUMMARYObjective: Inhibition of the mammalian target of rapamycin (mTOR) pathway has been suggested as a possible antiepileptogenic strategy in temporal lobe epilepsy (TLE). Here we aim to elucidate whether mTOR inhibition has antiepileptogenic and/ or antiseizure effects using different treatment strategies in the electrogenic poststatus epilepticus (SE) rat model. Methods: Effects of mTOR inhibitor rapamycin were tested using the following three treatment protocols: (1) "stop-treatment"-post-SE treatment (6 mg/kg/ day) was discontinued after 3 weeks; rats were monitored for 5 more weeks thereafter, (2) "pretreatment"-rapamycin (3 mg/kg/day) was applied during 3 days preceding SE; and (3) "chronic phase-treatment"-5 days rapamycin treatment (3 mg/kg/day) in the chronic phase. We also tested curcumin, an alternative mTOR inhibitor with antiinflammatory and antioxidant effects, using chronic phase treatment. Seizures were continuously monitored using video-electroencephalography (EEG) recordings; mossy fiber sprouting, cell death, and inflammation were studied using immunohistochemistry. Blood was withdrawn regularly to assess rapamycin and curcumin levels with high performance liquid chromatography (HPLC). Results: Stop-treatment led to a strong reduction of seizures during the 3-week treatment and a gradual reappearance of seizures during the following 5 weeks. Three days pretreatment did not prevent seizure development, whereas 5-day rapamycin treatment in the chronic phase reduced seizure frequency. Washout of rapamycin was slow and associated with a gradual reappearance of seizures. Rapamycin treatment (both 3 and 6 mg/kg) led to body growth reduction. Curcumin treatment did not reduce seizure frequency or lead to a decrease in body weight. Significance: The present study indicates that rapamycin cannot prevent epilepsy in the electrical stimulation post-SE rat model but has seizure-suppressing properties as long as rapamycin blood levels are sufficiently high. Oral curcumin treatment had no effect on chronic seizures, possibly because it did not reach the brain at adequate levels.

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Section: Discussionmentioning

confidence: 99%

Effects of rapamycin and curcumin treatment on the development of epilepsy after electrically induced status epilepticus in rats

et al. 2016

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“…Recent studies have indicated that mTOR plays a role in the epileptogenic process in TS inasmuch as early treatment with the mTOR inhibitor rapamycin can prevent the development of epilepsy in mice with conditional inactivation of the Tsc1 gene [114]. A retrospective clinical study confirmed the potential utility of rapamycin for the treatment of seizures in children with TSC; whether this action is disease-modifying remains to be determined [115]. Interestingly, mTOR dysregulation has been demonstrated in a variety of other types of epilepsy, including epilepsies associated with brain injury, SE, genetic mutations, brain tumors, and focal cortical dysplasias [116].…”

Section: The Mammalian Target Of Rapamycin Pathwaymentioning

confidence: 98%

The Potential of Antiseizure Drugs and Agents that Act on Novel Molecular Targets as Antiepileptogenic Treatments

2014

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A major goal of contemporary epilepsy research is the identification of therapies to prevent the development of recurrent seizures in individuals at risk, including those with brain injuries, infections, or neoplasms; status epilepticus; cortical dysplasias; or genetic epilepsy susceptibility. In this review we consider the evidence largely from preclinical models for the antiepileptogenic activity of a diverse range of potential therapies, including some marketed antiseizure drugs, as well as agents that act by immune and inflammatory mechanisms; reduction of oxidative stress; activation of the mammalian target of rapamycin or peroxisome proliferatoractivated receptors γ pathways; effects on factors related to thrombolysis, hematopoesis, and angiogenesis; inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reducatase; brainderived neurotrophic factor signaling; and blockade of α2 adrenergic and cannabinoid receptors. Antiepileptogenesis refers to a therapy of which the beneficial action is to reduce seizure frequency or severity outlasting the treatment period. To date, clinical trials have failed to demonstrate that antiseizure drugs have such disease-modifying activity. However, studies in animal models with levetiracetam and ethosuximide are encouraging, and clinical trials with these agents are warranted. Other promising strategies are inhibition of interleukin 1β signaling by drugs such as VX-765; modulation of sphingosine 1-phosphate signaling by drugs such as fingolimod; activation of the mammalian target of rapamycin by drugs such as rapamycin; the hormone erythropoietin; and, paradoxically, drugs such as the α2 adrenergic receptor antagonist atipamezole and the CB1 cannabinoid antagonist SR141716A (rimonabant) with proexcitatory activity. These approaches could lead to a new paradigm in epilepsy drug therapy where treatment for a limited period prevents the occurrence of spontaneous seizures, thus avoiding lifelong commitment to symptomatic treatment.

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“…In another study in which 7 patients with tuberous sclerosis complex who received everolimus or sirolimus treatment were examined, it was reported that mTOR inhibitors were efficient in resistant epilepsy (41). In a study performed in our country, it was reported that rapamycine was given to 7 of 86 patients with a diagnosis of tuberous sclerosis complex with different reasons, 5 of these patients had resistant seizures and all patients were free of seizure after a 6-month treatment period (42). Sirolimus treatment was given to 45% of the patients becasue of SEGA or angiomyolipomas.…”

Section: B Clinical Diagnostic Criteriamentioning

confidence: 99%

Tuberous sclerosis complex; a single center experience

Erol¹,

Savaş²,

Şekerci³

et al. 2015

Turk Arch Ped

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Aim: This study was planned with the aim of retrospectively reviewing the clinical and laboratory findings and therapies of our patients diagnosed with tuberous sclerosis and redefining the patients according to the diagnostic criteria revised by the 2012 International Tuberous Sclerosis Complex Consensus Group and comparing them with the literature. Material and Methods: Twenty patients diagnosed with tuberous sclerosis complex in the Pediatric Neurology Clinic were examined retrospectively in terms of clinical findings and therapies. The diagnoses were compared again according to 1998 and 2012 criteria. Results: It was observed that the complaint at presentation was seizure in 17 of 20 patients and hypopigmented spots on the skin in 3 of 20 patients. On the initial physical examination, findings related with the disease were found in the skin in 17 of the patients, in the eye in 5, in the kidneys in 7 and in the brain with imaging in 17. No cardiac involvement was observed in the patients. Infantile spasm was observed in 7 of the patients who presented because of seizure (n=17), partial seizure was observed in 7 and multiple seizure types were observed in 3. It was found that sirolimus treatment was given to 9 of 20 patients because of different reasons, 7 of these 9 patients had epileptic seizures and sirolimus treatment had no effect on epileptic seizures. According to 2012 diagnostic criteria, no marked change occured in the diagnoses of our patients. Conclusions: It was observed that the signs and symptoms of our patients were compatible with the literature. Molecular genetic examination was planned for the patients who were being followed up because of probable tuberous sclerosis complex. It was observed that sirolimus treatment had no marked effect on the seizure frequency of our patients. (Türk Ped Arş 2015; 50: 51-60)

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Rapamycin has a beneficial effect on controlling epilepsy in children with tuberous sclerosis complex: results of 7 children from a cohort of 86

Cited by 38 publications

References 70 publications

Effects of rapamycin and curcumin treatment on the development of epilepsy after electrically induced status epilepticus in rats

Effects of rapamycin and curcumin treatment on the development of epilepsy after electrically induced status epilepticus in rats

The Potential of Antiseizure Drugs and Agents that Act on Novel Molecular Targets as Antiepileptogenic Treatments

Tuberous sclerosis complex; a single center experience

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