mTOR dysregulation and tuberous sclerosis-related epilepsy

Curatolo, Paolo; Moavero, Romina; Scheppingen, Jackelien van; Aronica, Eleonora

doi:10.1080/14737175.2018.1428562

Cited by 78 publications

(81 citation statements)

References 230 publications

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“…This early hyperactivation of mTOR might lead to abnormalities of migration and orientation of neural cells, leading to abnormal cortical lamination and dendritic arborization. They are dynamic lesions, and changes within tubers, through pre-and postnatal life, may contribute to the establishment of extensive epileptogenic networks (Curatolo, Moavero, Van Scheppingen, & Aronica, 2018). This corresponds to an imbalance between excitation and inhibition, which is an obvious predisposing factor to epileptic seizures (Curatolo, 2015).…”

Section: Pathogenesis Of Epilepsy In Tscmentioning

confidence: 99%

Current concepts on epilepsy management in tuberous sclerosis complex

Canevini

Curatolo

Briola

et al. 2018

American J of Med Genetics Pt C

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Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disease affecting approximately 1 in 6,000 people, and represents one of the most common genetic causes of epilepsy. Epilepsy affects 90% of the patients and appears in the first 2 years of life in the majority of them. Early onset of epilepsy in the first 12 months of life is associated with high risk of cognitive decline and neuropsychiatric problems including autism. Prenatal or early infantile diagnosis of TSC, before the onset of epilepsy, provides a unique opportunity to monitor EEG before the onset of clinical seizures, thus enabling early intervention in the process of epileptogenesis. In this review, we discuss the current status of knowledge on epileptogenesis in TSC, and present recommendations of American and European experts in the field of epilepsy.

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Section: Pathogenesis Of Epilepsy In Tscmentioning

confidence: 99%

Current concepts on epilepsy management in tuberous sclerosis complex

Canevini

Curatolo

Briola

et al. 2018

American J of Med Genetics Pt C

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“…Interestingly, everolimus, as an immune-suppressor, inhibits mTOR signaling by reducing the phosphorylation of downstream mTOR effectos, has shown potential anti-epileptogenic activities [66][67][68]. Whether the potential effect of GA on epileptogenesis is involved in mTOR inhibition is worth clinical investigation.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

The Novel Effect of Immunomodulator-Glatiramer Acetate on Epileptogenesis and Epileptic Seizures

Lai

Lin

Yeh

et al. 2018

Cell Physiol Biochem

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Background/Aims: Immunological mechanisms can be triggered as a response to central nervous system insults and can lead to seizures. In this study an investigation was made to determine if glatiramer acetate (GA), an immunomodulator currently used in the treatment of multiple sclerosis, could protect rats from pilocarpine-induced seizures and chronic epilepsy. Methods: Two groups of adult male Sprague-Dawley rats, experimental (GA) and control, were used in the study. The systemic IL-1α and IL-1β levels at baseline were checked as well as status epilepticus (SE), and the spontaneous recurrent seizure (SRS) stage by enzyme-linked immunosorbent assay. The GA group was given GA (150 μg/kg, ip) and the control group was given a saline injection prior to pilocarpine-induced seizures. Seizure susceptibility, severity and mortality were evaluated, using Racine seizure classification and hippocampal damage was evaluated by Nissl staining. The GA group received GA (150 μg/kg/day, ip) daily after SE, and the chronic spontaneous seizures were evaluated by long-term video recording, and mossy fiber sprouting was evaluated by Timm staining. The IL-1α and IL-1β levels were correlated with seizure activities. The TNF-α level in the hippocampus was determined at the SRS stage by immunohistochemistry. The effect of GA on ionic currents and action potentials (APs) in NG108-15 differentiated neurons was investigated using patch-clamp technology. Results: It was found that latency to severe seizures was significantly longer in the GA (p < 0.01) group, which also had SE of shorter duration and less frequent SRS (p < 0.01). GA attenuated acute hippocampal neuron loss and chronic mossy fiber sprouting in the CA3 and the SRS-reduction correlated with the reduction of IL-1α, but not with IL-1β or TNF-α levels. Mechanistically, GA reduced the peak amplitude of voltage-gated Na⁺ current (I_Na), with a negative shift in the inactivation curve of I_Na and reduced the amplitude of APs along with decreased firing of APs. Conclusion: GA might serve as a neuroexcitability modulator which attenuates pilocarpine-induced acute and chronic excitotoxicity. Sodium channel attenuation was partially independent of the immunomodulatory effect.

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“…The cellular signaling pathway known as mammalian target of rapamycin (mTOR) is a key regulator of many integrated physiological functions, including proper neuronal network development, synaptic plasticity, and cognition. Tuberous sclerosis complex (TSC) is a monogenic disorder of mTOR regulation that provides a mechanistic basis for a direct link between gene mutation and brain pathology . TSC1 and TSC2 mutations, which cause TSC, are associated with overactivation of the mTOR pathway that can lead to epileptogenic cerebral dysplasia and encephalopathy.…”

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confidence: 99%