Cortical GABAergic Interneuron/Progenitor Transplantation as a Novel Therapy for Intractable Epilepsy

Zhu, Qian; Naegele, Janice R.; Chung, Sangmi

doi:10.3389/fncel.2018.00167

Cited by 25 publications

(20 citation statements)

References 80 publications

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“…Deficits in the number, migration, and positioning of cortical GABAergic inhibitory interneurons may lead to an imbalance of excitatory-inhibitory activity associated with overlapping neurological and neurodevelopmental disorders including epilepsy and autism [41][42][43].…”

Section: The Emerging Role Of Mtor-dependent Autophagy In the Regulatmentioning

confidence: 99%

“…Recently, increasing evidence indicates a functional cross-talk between UPS and autophagy, which occurs at both biochemical and morphological levels [28,[38][39][40][41][42][43][44][45][46][47][48][49]. This is largely due to the mTOR pathway, which modulates both UPS-and autophagy-dependent protein degradation [30].…”

Section: A Glance At Mtor-related Ups Alterations In Epilepsymentioning

confidence: 99%

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mTOR-Related Cell-Clearing Systems in Epileptic Seizures, an Update

Limanaqi

Biagioni

Busceti

et al. 2020

IJMS

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Recent evidence suggests that autophagy impairment is implicated in the epileptogenic mechanisms downstream of mTOR hyperactivation. This holds true for a variety of genetic and acquired epileptic syndromes besides malformations of cortical development which are classically known as mTORopathies. Autophagy suppression is sufficient to induce epilepsy in experimental models, while rescuing autophagy prevents epileptogenesis, improves behavioral alterations, and provides neuroprotection in seizure-induced neuronal damage. The implication of autophagy in epileptogenesis and maturation phenomena related to seizure activity is supported by evidence indicating that autophagy is involved in the molecular mechanisms which are implicated in epilepsy. In general, mTOR-dependent autophagy regulates the proliferation and migration of inter-/neuronal cortical progenitors, synapse development, vesicular release, synaptic plasticity, and importantly, synaptic clustering of GABAA receptors and subsequent excitatory/inhibitory balance in the brain. Similar to autophagy, the ubiquitin–proteasome system is regulated downstream of mTOR, and it is implicated in epileptogenesis. Thus, mTOR-dependent cell-clearing systems are now taking center stage in the field of epilepsy. In the present review, we discuss such evidence in a variety of seizure-related disorders and models. This is expected to provide a deeper insight into the molecular mechanisms underlying seizure activity.

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Section: The Emerging Role Of Mtor-dependent Autophagy In the Regulatmentioning

confidence: 99%

Section: A Glance At Mtor-related Ups Alterations In Epilepsymentioning

confidence: 99%

mTOR-Related Cell-Clearing Systems in Epileptic Seizures, an Update

Limanaqi

Biagioni

Busceti

et al. 2020

IJMS

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“…There is urgent need to develop new therapies that directly target epileptic foci restoring proper inhibition and synchronicity, rather than more systemic interventions [93,113]. One strategy that has been proposed in recent years is to restore normal circuit function by transplanting cells capable to differentiate into GABAergic neuronsat the seizure focus.…”

Section: Advances In the Use Of Gaba-committed Progenitors In Models mentioning

confidence: 99%

“…Furthermore, patients that respond to AEDs typically face serious adverse side effects [5]. Surgical removal of affected brain tissues or implanting neurostimulator devices are effective options only for a fraction of drug-refractory patients [6]. Furthermore, current treatments of epilepsy often enhance some of the de icits in cognitive functions typically associated with epilepsy, leading to poor compliance [7].…”

Section: Introductionmentioning

confidence: 99%

Advances in the use of GABAergic interneurons for the treatment of epilepsy

Frisina¹,

Valetti²,

Zuccarini³

et al. 2019

J Stem Cell Ther Transplant

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Forebrain GABAergic neurons, the main inhibitory type of neuron in the cortex and hippocampus, represent a highly heterogeneous cell population that has been implicated in the predisposition to epilepsy and the onset of seizure. Earlier attempts to restore inhibition and reduce seizure in animal models of epilepsy have been carried out using embryonic basal forebrain tissue as source of immature GABAergic progenitors in cell-based therapies, with promising results. For therapeutic strategies this approach appears unrealistic, while the use of pluripotent stem cells to obtain immature GABAergic neurons opens new and promising avenues. Research on neural stem cells and pluripotent stem cells has greatly advanced and protocols have been established to effi ciently direct progenitor cells to differentiate towards the GABAergic lineage. However, being highly heterogeneous, these neurons are diffi cult to be fully represented in vitro. Better knowledge on the expressed gene profi les, at single cell level, and the differentiation trajectory of these neurons will consent a more precise monitoring of the differentiation steps. Here we review the current literature about how to obtain and characterize genuine inhibitory neurons, how these can be grafted in animal models (and one day possibly in human) and which diseases could potentially be targeted and the effi ciency of therapeutic outcome. The main obstacles that need to be overcome are: a) choice of an appropriate animal model, b) availability of human cells prone to GABA differentiation, c) the full representation of all IN subtypes, their proportions and their physiological activities, d) how to monitor them on the long-term after transplant.

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“…Epilepsy is a neurological disorder where the recurrent seizure occurs due to the abnormal electrical firing 1,2 . These seizures occur as episodes which can vary from brief and almost undetectable to a long period of vigorous shaking.…”

Section: Introductionmentioning

confidence: 99%

Untitled

2019

IJPSR

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Memory impairment (MI) is commonly seen in epilepsy and is at times aggravated by antiepileptic therapy. Recent studies reported that coadministration of nootropic agent with an antiepileptic drug (AED) might decrease the MI. This study was designed to evaluate MI activity of Eslicarbazepine (ESL) in temporal lobe epilepsy (TLE) and to assess the protective effect of Nefiracetam (NEF) which is a racetam group nootropic. MI activity was evaluated by radial arm maze (RAM) on lithium-pilocarpine induced TLE in Wistar Albino Rats. Antiepileptic activity of ESL was also assessed in the absence and presence of NEF. ESL treated a group of animals had increased errors in RAM, compared to the control group which indicated the presence of MI. The extent of MI was decreased when given a half dose of ESL. ESL aggravated the MI in epileptic rats which was very much similar to phenytoin, a standard more than the control group. Coadministration of NEF reversed the MI induced by ESL significantly. It was also observed that NEF treated animals have shown activity as that of the normal group of animals, demonstrating that NEF ameliorates MI in TLE. The anticonvulsant activity was found to be synergized due to the co-administration of NEF when compared to control, and ESL alone treated animals. The combination of a reduced dose of ESL and Nefiracetam was very potent compared to ESL and Phenytoin alone. The reduced dose of ESL and NEF showed a very synergistic effect as nootropic without altering the Anti-epileptic activity.

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Cortical GABAergic Interneuron/Progenitor Transplantation as a Novel Therapy for Intractable Epilepsy

Cited by 25 publications

References 80 publications

mTOR-Related Cell-Clearing Systems in Epileptic Seizures, an Update

mTOR-Related Cell-Clearing Systems in Epileptic Seizures, an Update

Advances in the use of GABAergic interneurons for the treatment of epilepsy

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