Transplantation of GABA-Producing Cells for Seizure Control in Models of Temporal Lobe Epilepsy

Abstract

Summary:A high percentage of patients with temporal lobe epilepsy (TLE) are refractory to conventional pharmacotherapy. The progressive neurodegenerative processes associated with a lifetime of uncontrolled seizures mandate the development of alternative approaches to treat this disease. Transplantation of inhibitory cells has been suggested as a potential therapeutic strategy to achieve seizure suppression in humans with intractable TLE. Preclinical investigations over 20 years have demonstrated that multiple cell types from several sources can produce anticonvulsant, and antiepileptogenic, effects in animal models of TLE. Transplanting GABA-producing cells, in particular, has been shown to reduce seizures in several well-established models. This review addresses experimentation using different sources of transplantable GABAergic cells, highlighting progress with fetal tissue, neural cell lines, and stem cells. Regardless of the source of the GABAergic cells used in seizure studies, common challenges have emerged. Several variables influence the anticonvulsant potential of GABA-producing cells. For example, tissue availability, graft survival, immunogenicity, tumorigenicity, and varying levels of cell migration, differentiation, and integration into functional circuits and the microenvironment provided by sclerotic tissue all contribute to the efficacy of transplanted cells. The challenge of understanding how all of these variables work in concert, in a disease process that has no well-established etiology, suggests that there is still much basic research to be done before rational cell-based therapies can be developed for TLE.

Progress in Cell Grafting Therapy for Temporal Lobe Epilepsy

“…In addition, the plasticity of surviving neurons and the circuitry of a fraction of newly born dentate granule cells after the injury appear to be detrimental toward normalizing the hippocampal function after injury [24,27,33,34]. These issues have provided an impetus for replacing lost neurons through grafting of fresh hippocampal precursor cells obtained from the fetal brain or NSCs/neuronal progenitors expanded from diverse sources in animal models of hippocampal injury and TLE [25,[27][28][29][30]. Grafting of specific post-mitotic hippocampal precursor cells shortly after hippocampal injury or SE has significance, because such an approach has promise for replacing the lost neurons, as well as facilitating the reconstruction the disrupted hippocampal circuitry [14,24,25,35,36].…”

“…This is because: 1) GABA-ergic function is reduced in TLE [6,8,9,15,48]; 2) grafting of cells that just release GABA can facilitate transient anti-seizure effects [28,29,53,56,88]; 3) axons of GABA-ergic neurons derived from the MGE cell grafts exhibit a high propensity for increasing the extent of inhibition in the normal postnatal brain [59,86]; and 4) increased GDNF levels in the epileptic brain restrain SRS [89,90]. However, rigorous electrophysiological, electron-microscopic, and biochemical studies are needed in the future to confirm these possibilities.…”

“…In this context, cell transplantation approach has promise in serving as an adept alternate therapy for TLE. This is because this strategy has shown the capability to curb epileptogenesis (the succession that modifies a normal brain region into an epileptic precinct) when employed soon after an IPI, and to contain SRS when utilized after the occurrence of TLE in pre-clinical studies [24][25][26][27][28][29][30]. Because the seizuregenerating zone and the associated cell loss are mainly localized to the hippocampus in most cases, TLE appears to be good candidate to treat it with the cell transplantation approach.…”

Effects of Intravenous Human Umbilical Cord Blood Mesenchymal Stem Cell Therapy versus Gabapentin in Pentylenetetrazole-Induced Chronic Epilepsy in Rats

“…In patients refractive to treatment, brain surgery is the most important alternative treatment; however, surgery includes risks and costs that have to be considered. Pharmacotherapy has a high success rate in terms of seizure relief, but it comes with the cost of a frequent reliance on toxicity and memory deficits as reported in many studies [3]. …”

“…Stem cell transplantation benefits are now attributed to an attenuation of inflammation, a neuroprotection of the damaged milieu through growth factor and chemokine secretion to promote cell survival and proliferation, and an enhancement of endogenous recovery processes [7]. In chronic epilepsy, human pluripotent cell-derived neural stem cells have been reported to migrate into the injured dentate gyrus and differentiate into neurons, glia, and predifferentiated GABA-ergic cells [3,5]. …”