Novel therapeutic approaches for disease-modification of epileptogenesis for curing epilepsy

Clossen, Bryan L.; Reddy, Doodipala Samba

doi:10.1016/j.bbadis.2017.02.003

Cited by 91 publications

(57 citation statements)

References 299 publications

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“…Possible future treatments with rapamycin, or other mTOR inhibitors, may be promising for the prevention of neurocognitive manifestations, including epilepsy, but still needs to be tested. 32 In conclusion, SKS, caused by germline or mosaic mutations in the mTOR gene, is a recently described and clinically discernible disorder characterized mainly by ID, macrocephaly/hemi/megalencephaly, and seizures. Facial dysmorphism and other non-neurological manifestations, may also provide diagnostic clues in some individuals.…”

Section: Discussionmentioning

confidence: 99%

mTOR mutations in Smith‐Kingsmore syndrome: Four additional patients and a review

et al. 2018

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Smith‐Kingsmore syndrome (SKS) OMIM #616638, also known as MINDS syndrome (ORPHA 457485), is a rare autosomal dominant disorder reported so far in 23 patients. SKS is characterized by intellectual disability, macrocephaly/hemi/megalencephaly, and seizures. It is also associated with a pattern of facial dysmorphology and other non‐neurological features. Germline or mosaic mutations of the mTOR gene have been detected in all patients. The mTOR gene is a key regulator of cell growth, cell proliferation, protein synthesis and synaptic plasticity, and the mTOR pathway (PI3K‐AKT‐mTOR) is highly regulated and critical for cell survival and apoptosis. Mutations in different genes in this pathway result in known rare diseases implicated in hemi/megalencephaly with epilepsy, as the tuberous sclerosis complex caused by mutations in TSC1 and TSC2, or the PIK3CA‐related overgrowth spectrum (PROS). We here present 4 new cases of SKS, review all clinical and molecular aspects of this disorder, as well as some characteristics of the patients with only brain mTOR somatic mutations.

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Section: Discussionmentioning

confidence: 99%

mTOR mutations in Smith‐Kingsmore syndrome: Four additional patients and a review

et al. 2018

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“…The resulting seizures alter patients’ perception, consciousness, memory and motor activity. There are a significant number of antiepileptic drugs (AED) on the market, however these therapeutic agents are only aimed at controlling the seizures; there are no disease-modifying therapies available (reviewed in [ 2 ]). In other words, the AED target only the disease symptoms, and fail to adequately prevent seizure development, or permanently halt the occurrence of seizures [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Early Gabapentin Treatment during the Latency Period Increases Convulsive Threshold, Reduces Microglial Activation and Macrophage Infiltration in the Lithium-Pilocarpine Model of Epilepsy

et al. 2017

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The lithium-pilocarpine model of epilepsy reproduces several features of temporal lobe epilepsy in humans, including the chronological timeline of an initial latency period followed by the development of spontaneous seizures. Epilepsy therapies in humans are implemented, as a rule, after the onset of the spontaneous seizures. We here studied the potential effect on epileptogenesis of starting an early treatment during the latency period, in order to prevent the development of spontaneous seizures. Adult male Wistar rats were treated with 3 mEq/kg LiCl, and 20 h later 30 mg/kg pilocarpine. Once status epilepticus (SE) was achieved, it was allowed to last for 20 min, and then motor seizures were controlled with the administration of 20 mg/kg diazepam. At 1DPSE (DPSE, days post-status epilepticus), animals started to receive 400 mg/kg/day gabapentin or saline for 4 days. At 5DPSE, we observed that SE induced an early profuse microglial and astroglial reactivity, increased synaptogenic trombospondin-1 expression and reduced AQP4 expression in astroglial ending feet. Blood brain barrier (BBB) integrity seemed to be compromised, as infiltrating NG2+ macrophages and facilitated access to the CNS was observed by transplanting eGFP+ blood cells and bone marrow-derived progenitors in the SE animals. The early 4-day gabapentin treatment successfully reduced microglial cell reactivity and blood-borne cell infiltration, without significantly altering the mRNA of proinflammatory cytokines IL-1β and TNFα immediately after the treatment. After 21DSPE, another group of animals that developed SE and received 4 days of gabapentin treatment, were re-exposed to subconvulsive accumulative doses of pilocarpine (10 mg/kg/30 min) and were followed by recording the Racine scale reached. Early 4-day gabapentin treatment reduced the Racine scale reached by the animals, reduced animal mortality, and reduced the number of animals that achieved SE (34% vs. 72%). We conclude that early gabapentin treatment following SE, during the latency period, is able to reduce neuroinflammation and produces a persistent effect that limits seizures and increases convulsive threshold, probably by restricting microglial reactivity and spurious synaptogenesis.

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“…These precipitating factors activate various signaling events such as inflammation, oxidation, apoptosis, neurogenesis and synaptic plasticity, subsequently leading to structural and functional changes in neurons. These changes eventually manifest as abnormal hyperexcitability and spontaneous seizures [28]. Preventive approach to epilepsy is quite a novel concept and few methods have been tried to date.…”

Section: Discussionmentioning

confidence: 99%

Age at onset and response to antiepileptic drugs in patients with various subtypes of idiopathic generalized epilepsy - preliminary investigation for the prevention of epilepsy

Takagi

Yamamoto

Hara

et al. 2018

E&S

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Purpose: Epilepsy is a common neur ological disease that places sever e bur dens on patients over a ver y long period. Current treatments mainly involve antiepileptic drugs, but these do not cure epilepsy. Improvements in treatment methods and targets have thus been awaited. Antiepileptic drugs given before the onset of epilepsy have been shown to exert beneficial effects on epilepsy prognosis in rodent and human studies. To establish preventive approaches to epilepsy, we organized a study team to clarify the mean age at onset of each epilepsy phenotype classified into genetic generalized epilepsy. Methods: Patients with genetic gener alized epilepsy including epilepsy with gener alized tonic-clinic seizures on awakening, juvenile myoclonic epilepsy, juvenile absence epilepsy and childhood absence epilepsy, who visited our institutes between 2014 to 2016 were studied. Demographic data from these patients and their offspring were analyzed. Offspring were regarded as a high-risk group because of high hereditability of epilepsy. Results: The study population compr ised 154 patients (gener alized tonic-clonic seizures on awakening, n=76; juvenile myoclonic epilepsy, n=52; juvenile absence epilepsy, n=17; childhood absence epilepsy, n=9) and 30 offspring. Mean (±standard deviation) age of patients was 27.78±9.69 years. Mean age at onset was 16.05±6.44 years, and mean duration of disease was 11.36±9.84 years. A high rate of multiple antiepileptic drug use and long duration of disease were found in all types of epilepsy studied. Conclusion: This preliminar y study highlights the necessity for identification of offspr ing war r anting ear ly treatment together with optimal timing of such treatment. Abstract

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Novel therapeutic approaches for disease-modification of epileptogenesis for curing epilepsy

Cited by 91 publications

References 299 publications

mTOR mutations in Smith‐Kingsmore syndrome: Four additional patients and a review

mTOR mutations in Smith‐Kingsmore syndrome: Four additional patients and a review

Early Gabapentin Treatment during the Latency Period Increases Convulsive Threshold, Reduces Microglial Activation and Macrophage Infiltration in the Lithium-Pilocarpine Model of Epilepsy

Age at onset and response to antiepileptic drugs in patients with various subtypes of idiopathic generalized epilepsy - preliminary investigation for the prevention of epilepsy

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