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Electrophoretic Delivery of γ-aminobutyric Acid GABA into Epileptic Focus Prevents Seizures in Mice
Published on: May 16, 2019
Persistent seizure control in epileptic mice transplanted with gamma-aminobutyric acid progenitors
Mariana L Casalia1, MacKenzie A Howard1, Scott C Baraban1
1Epilepsy Research Laboratory, Department of Neurological Surgery and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA.
Objective:
A significant proportion of the more than 50 million people worldwide 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% to 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 intrahippocampal 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 6 months after treatment. Ann Neurol 2017;82:530-542.
Insights
Transplanting medial ganglionic eminence (MGE) progenitor cells into the brain effectively reduced seizures and improved behavior in an epilepsy model. This cell therapy offers a promising alternative for drug-resistant epilepsy patients.
Area of Science:
- Neuroscience
- Regenerative Medicine
- Epilepsy Research
Background:
- Epilepsy affects over 50 million people globally, with many cases resistant to antiepileptic drugs (AEDs).
- Cell transplantation presents a novel therapeutic strategy for long-term modification of epileptic neural circuits.
- Preclinical studies in chronic epilepsy models are crucial for developing effective cell-based treatments.
Purpose of the Study:
- To evaluate the efficacy of medial or caudal ganglionic eminence (MGE, CGE) progenitor cell transplantation in a mouse model of chronic epilepsy.
- To assess the impact of cell transplantation on seizure activity, behavioral deficits, and hippocampal function.
Main Methods:
- MGE and CGE progenitor cells were transplanted into the hippocampus of mice with pilocarpine-induced epilepsy.
- Behavioral tests, video-electroencephalographic monitoring, and slice electrophysiology were performed up to 270 days post-transplantation.
- Immunohistochemistry confirmed cell identity.
Main Results:
- MGE progenitor transplantation rescued handling and open field deficits starting at 60 days post-transplantation.
- Seizure activity was reduced by 84-88% between 180 and 210 days post-transplantation in MGE-treated mice.
- MGE transplants restored inhibitory postsynaptic current frequency in pyramidal neurons to naive levels; CGE transplants showed no seizure reduction.
Conclusions:
- Transplanted MGE progenitors enhance GABA-mediated inhibition and reduce seizure frequency in a chronic epilepsy model.
- Cell therapy with MGE progenitors rescues behavioral deficits for over six months post-treatment.
- This study supports MGE progenitor cell transplantation as a viable therapeutic approach for drug-resistant epilepsy.
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