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

Abstract

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.

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

“…Two months after grafting, the animals showed seizures suppression and rescue of behavioral comorbidities; at 6 months seizures frequency was reduced by 84% and at 12 months the seizures total number was reduced by 88%. The authors also documented enhancement of GABAergic IN-mediated currents suggesting a functional integration in the host network [118].…”

“…Adopting a similar experimental paradigm, another study used freshly dissociated MGE-derived progenitors grafted in a model of pilocarpin-induced seizure, and monitored the effect at 7 and 12 months after transplantation [118]. At 7 months, the grafted cells were differentiated into GAD67 + neurons expressing SST, PV and nNOS (Table 1).…”

“…Electrophysiological recordings reveal that exogenous INs functionally integrate in the host circuity providing increased inhibitory activity, although not all authors investigated this aspect. Importantly, the anticonvulsant ef icacy of grafted cells seems to largely depend on the mode of collecting and expanding these cells: whether from primary dissociated MGE embryonic tissues [110,115,[118][119][120], from neurosphere-expanded MGE progenitors [119,121], from differentiated hIPSC [92,93,112], or from hNSC [31]. Among these, the use of dissociated MGE cells seems to be the most valid and applied strategy.…”

Microglial polarization in posttraumatic epilepsy: Potential mechanism and treatment opportunity

“…Cellular therapies, especially with stem cells of different regenerative capacities, have been trialed in neurological disorders with chronic loss of specific cell types, such as Parkinson disease and Alzheimer disease, as well as brain injury associated with ongoing neurodegeneration such as stroke and TBI . Such therapies have also shown promising outcomes in epilepsy models administering the stem cells programmed to differentiate into GABAergic interneurons to counter the excessive network excitability . Genetically modified cells have also been injected into the brain to continuously deliver different neuropeptides or other molecules with antiepileptic potential and have shown positive outcomes .…”

“…96 Such therapies have also shown promising outcomes in epilepsy models administering the stem cells programmed to differentiate into GABAergic interneurons to counter the excessive network excitability. 97,98 Genetically modified cells have also been injected into the brain to continuously deliver different neuropeptides or other molecules with antiepileptic potential and have shown positive outcomes. 99,100 In addition, different types of stem cells, such as MSCs (multipotent cells of stromal origin) and neural stem cells (multipotent cells with the capacity to generate into neurons and glial cells), have been observed to interact with the host cells by the exchange of trophic growth factors and modulation of immune response.…”