GABA-ergic cell therapy for epilepsy: Advances, limitations and challenges

Shetty, Ashok K.; Upadhya, Dinesh

doi:10.1016/j.neubiorev.2015.12.014

Cited by 78 publications

(95 citation statements)

References 88 publications

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“…Although it has been suggested that seizure suppressive effects of MGE progenitor cell transplantation may be transient 18,25 , here starting at 180 DAT, and in our earlier publications at 45 and 60 DAT 14,17 we have found absolutely no evidence to support this conclusion. There are at least two potential explanations for this discrepancy.…”

Section: Discussioncontrasting

confidence: 90%

“…Using a well-characterized pilocarpine model of acquired epilepsy, we also demonstrated that MGE progenitors transplanted into adult hippocampus reduced unprovoked seizures by 90% starting at 60 DAT 14 . While our studies strongly support continued preclinical development of MGE progenitor transplantation as a therapy for intractable epilepsies, other groups suggested these effects may be transient 18,24,25 and CGE-based cell transplantation for epilepsy has not been studied.…”

Section: Introductionsupporting

confidence: 52%

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Persistent seizure control in epileptic mice transplanted with gamma‐aminobutyric acid progenitors

Casalia

Howard

Baraban

2017

Annals of Neurology

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Objective A significant proportion of the more than 50 million people world-wide currently suffering with epilepsy are resistant to antiepileptic drugs (AEDs). As an alternative to AEDs, novel therapies based on cell transplantation offer an opportunity for long-lasting modification of epileptic circuits. To develop such a treatment requires careful preclinical studies in a chronic epilepsy model featuring unprovoked seizures, hippocampal histopathology, and behavioral comorbidities. Methods Transplantation of progenitor cells from embryonic medial or caudal ganglionic eminence (MGE, CGE) were made in a well-characterized mouse model of status epilepticus-induced epilepsy (systemic pilocarpine). Behavioral testing (handling and open field), continuous video-electroencephalographic (vEEG) monitoring and slice electrophysiology outcomes were obtained up to 270 days after transplantation (DAT). Post hoc immunohistochemistry was used to confirm cell identity. Results MGE progenitors transplanted into the hippocampus of epileptic mice rescued handling and open field deficits starting at 60 DAT. In these same mice, an 84–88% reduction in seizure activity was observed between 180 and 210 DAT. Inhibitory postsynaptic current frequency, measured on pyramidal neurons in acute hippocampal slices at 270 DAT, was reduced in epileptic mice but restored to naïve levels in epileptic mice receiving MGE transplants. No reduction in seizure activity was observed in epileptic mice receiving intra-hippocampal CGE progenitors. Interpretation Our findings demonstrate that transplanted MGE progenitors enhance functional GABA-mediated inhibition, reduce spontaneous seizure frequency and rescue behavioral deficits in a chronic epileptic animal model more than six months after treatment.

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Section: Discussioncontrasting

confidence: 90%

Section: Introductionsupporting

confidence: 52%

Persistent seizure control in epileptic mice transplanted with gamma‐aminobutyric acid progenitors

Casalia

Howard

Baraban

2017

Annals of Neurology

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“…23,24) On the other hand, dysfunction in neurotransmission mediated by the inhibitory neurotransmitter GABA is related to the onset and development of several neurological disorders including epilepsy and insomnia. 25,26) The high-affinity transporters for glutamic acid and GABA are EAAT and GAT, respectively, but the low-affinity transporters are unclear. Glutamic acid and GABA are amino acids and zwitterionic compounds.…”

Section: Physiological Roles Of Organic Cation Transporters In Neuronsmentioning

confidence: 99%

Physiological Roles of Carnitine/Organic Cation Transporter OCTN1/SLC22A4 in Neural Cells

Nakamichi

Kato

2017

Biological & Pharmaceutical Bulletin

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Dysfunction in neurotransmission mediated by neurotransmitters causes various neurological disorders.Therefore, receptors and reuptake transporters of neurotransmitters have been focused on as a therapeutic target in neurological disorders. These membrane proteins have high affinity for a specific neurotransmitter and are highly expressed on synaptic membranes. In contrast, xenobiotic transporters have relatively lower affinity for neurotransmitters but widely recognize various organic cations and/or anions and are also expressed in brain neurons. However, it has been largely unknown why such xenobiotic transporters are expressed in neurons that play a key role in signal transduction. We have therefore attempted to clarify the physiological roles of one such xenobiotic organic cation transporter (OCT) in neural cells with the aim of obtaining new insight into the treatment of neurological disorders. Carnitine/organic cation transporter OCTN1/SLC22A4 is functionally expressed in neurons and neural stem cells. In particular, OCTN1 is expressed at much higher levels compared with other OCTs in neural stem cells and positively regulates their differentiation into neurons. OCTN1 accepts the naturally occurring food-derived antioxidant ergothioneine (ERGO) as a good in vivo substrate. Because ERGO is highly distributed into the brain after oral ingestion, OCTN1 may contribute to the alleviation of oxidative stress and promotion of neuronal differentiation via the uptake of ERGO in the brain, perhaps abating symptoms of neurological disorders. In this review, we introduce current topics on the physiological roles of OCTs with a focus on OCTN1 in neural cells and discuss its possible application to the treatment of neurological disorders.

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“…Exploring these complex avenues will undoubtedly advance design of effective preventative strategies for a number of common, debilitating conditions. Furthermore, technical advances fueled by understanding of cIN development are quickly making cell culture and grafting therapies imaginable treatments for these devastating disorders 166,167 .…”

Section: Discussionmentioning

confidence: 99%

Gene-environment interactions in cortical interneuron development and dysfunction: A review of preclinical studies

Ansen-Wilson

Lipinski

2017

NeuroToxicology

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Cortical interneurons (cINs) are a diverse group of locally projecting neurons essential to the organization and regulation of neural networks. Though they comprise only ~20% of neurons in the neocortex, their dynamic modulation of cortical activity is requisite for normal cognition and underlies multiple aspects of learning and memory. While displaying significant morphological, molecular, and electrophysiological variability, cINs collectively function to maintain the excitatory-inhibitory balance in the cortex by dampening hyperexcitability and synchronizing activity of projection neurons, primarily through use of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Disruption of the excitatory-inhibitory balance is a common pathophysiological feature of multiple seizure and neuropsychiatric disorders, including epilepsy, schizophrenia, and autism. While most studies have focused on genetic disruption of cIN development in these conditions, emerging evidence indicates that cIN development is exquisitely sensitive to teratogenic disruption. Here, we review key aspects of cIN development, including specification, migration, and integration into neural circuits. Additionally, we examine the mechanisms by which prenatal exposure to common chemical and environmental agents disrupt these events in preclinical models. Understanding how genetic and environmental factors interact to disrupt cIN development and function has tremendous potential to advance prevention and treatment of prevalent seizure and neuropsychiatric illnesses.

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GABA-ergic cell therapy for epilepsy: Advances, limitations and challenges

Cited by 78 publications

References 88 publications

Persistent seizure control in epileptic mice transplanted with gamma‐aminobutyric acid progenitors

Persistent seizure control in epileptic mice transplanted with gamma‐aminobutyric acid progenitors

Physiological Roles of Carnitine/Organic Cation Transporter OCTN1/SLC22A4 in Neural Cells

Gene-environment interactions in cortical interneuron development and dysfunction: A review of preclinical studies

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