Vigabatrin Inhibits Seizures and mTOR Pathway Activation in a Mouse Model of Tuberous Sclerosis Complex

Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, United States of America.
PLoS ONE (Impact Factor: 3.23). 02/2013; 8(2):e57445. DOI: 10.1371/journal.pone.0057445
Source: PubMed


Epilepsy is a common neurological disorder and cause of significant morbidity and mortality. Although antiseizure medication is the first-line treatment for epilepsy, currently available medications are ineffective in a significant percentage of patients and have not clearly been demonstrated to have disease-specific effects for epilepsy. While seizures are usually intractable to medication in tuberous sclerosis complex (TSC), a common genetic cause of epilepsy, vigabatrin appears to have unique efficacy for epilepsy in TSC. While vigabatrin increases gamma-aminobutyric acid (GABA) levels, the precise mechanism of action of vigabatrin in TSC is not known. In this study, we investigated the effects of vigabatrin on epilepsy in a knock-out mouse model of TSC and tested the novel hypothesis that vigabatrin inhibits the mammalian target of rapamycin (mTOR) pathway, a key signaling pathway that is dysregulated in TSC. We found that vigabatrin caused a modest increase in brain GABA levels and inhibited seizures in the mouse model of TSC. Furthermore, vigabatrin partially inhibited mTOR pathway activity and glial proliferation in the knock-out mice in vivo, as well as reduced mTOR pathway activation in cultured astrocytes from both knock-out and control mice. This study identifies a potential novel mechanism of action of an antiseizure medication involving the mTOR pathway, which may account for the unique efficacy of this drug for a genetic epilepsy.

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Available from: Michael Wong, Dec 16, 2013
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    ABSTRACT: Background Tuberous Sclerosis Complex is a genetic multi-system disorder that affects the brain in almost every patient. It is caused by a mutation in the TSC1 or TSC2 genes, which regulate mTOR, a key player in control of cellular growth and protein synthesis. The most frequent neurologic symptoms are seizures, which occur in up to 90% of patients and are often intractable, followed by autism spectrum disorders, intellectual disability, ADHD and sleep problems. Conventional treatment has frequently proven insufficient for neurologic and behavioral symptoms, particularly seizure control. This review focuses on the role of TSC/mTOR in neuronal development and network formation, and recent mechanism-based treatment approaches. Methods We performed a literature review to identify ongoing therapeutical challenges and novel strategies. Results To achieve a better quality of life for many patients, current therapy approaches are directed at restoring dysregulated mTOR signaling. Animal studies have provided insight into aberrant neuronal network formation caused by constitutive activation of the mTOR pathway, and initial studies in TSC patients using MR diffusion tensor imaging and EEG support a model of impaired neuronal connectivity in TSC. Rapamycin, an mTOR inhibitor, has been used successfully in Tsc-deficient mice to prevent and treat seizures and behavioral abnormalities. There is recent evidence in humans of improved seizure control with mTOR inhibitors. Conclusions Current research provides insight into aberrant neuronal connectivity in TSC and the role of mTOR inhibitors as a promising therapeutical approach.
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    ABSTRACT: Dysregulation of the mTOR signaling pathway is associated with highly epileptogenic conditions such as tuberous sclerosis, focal cortical dysplasia, hemimegalencephaly and ganglioglioma, grouped under the term of 'mTORopathies'. Brain abnormalities associated with mTOR overactivation include enlarged and dysplastic neurons, abnormal cortical organization and astrogliosis. mTOR signaling intervenes in several molecular/biochemical processes leading to epileptogenesis. Animal models demonstrated that mTOR inhibitors could exert both an anticonvulsant action and an antiepileptogenic effect in models of genetic and acquired epilepsy. Preliminary studies in patients affected by tuberous sclerosis and treated with rapamycin or everolimus demonstrated potential benefits in seizure frequency reduction, suggesting that mTOR inhibition could be a promising treatment option for mTORopathies-related epilepsy. The authors reviewed the current knowledge of mTOR overactivation in different forms of epilepsy, and discuss the potential clinical use of mTOR inhibitors.
    Full-text · Article · Jun 2013 · Expert Review of Neurotherapeutics
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    ABSTRACT: Epilepsy, a common neurological disorder and cause of significant morbidity and mortality, places an enormous burden on the individual and society. Presently, most drugs for epilepsy primarily suppress seizures as symptomatic therapies but do not possess actual antiepileptogenic or disease-modifying properties. The mTOR (mammalian target of rapamycin) signaling pathway is involved in major multiple cellular functions, including protein synthesis, cell growth and proliferation and synaptic plasticity, which may influence neuronal excitability and be responsible for epileptogenesis. Intriguing findings of the frequent hyperactivation of mTOR signaling in epilepsy make it a potential mechanism in the pathogenesis as well as an attractive target for the therapeutic intervention, and have driven the significant ongoing efforts to pharmacologically target this pathway. This review explores the relevance of the mTOR pathway to epileptogenesis and its potential as a therapeutic target in epilepsy treatment by presenting the current results on mTOR inhibitors, in particular, rapamycin, in animal models of diverse types of epilepsy. Limited clinical studies in human epilepsy, some paradoxical experimental data and outstanding questions have also been discussed.
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