Intranigral transplants of a GABAergic cell line produce long-term alleviation of established motor seizures

Abstract

We have previously shown that intranigral transplants of immortalized GABAergic cells decrease the number of kainic acid-induced seizures [5] in an animal model. In the present study, recurrent NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript spontaneous behavioral seizures were established by repeated systemic injections of this excitotoxin into male Sprague Dawley rats. After the seizures had been established, cells were transplanted into the substantia nigra. Animals with transplants of control cells (without hGAD67 expression) or with sham transplants showed a death rate of more than 40% over the 12 weeks of observation, whereas in animals with M213-2O Cl4 transplants, the death rate was reduced to less than 20%. The M213-2O Cl4 transplants significantly reduced the percentage of animals showing behavioral seizures; animals with these transplants also showed a lower occurrence of stage V seizures than animals in the other groups. In vivo and in vitro analyses provided evidence that the GABAergic cells show sustained expression of both GAD67 and hGAD67cDNA, as well as increased GABA levels in the ventral mesencephalon of transplanted animals. Therefore, transplantation of GABA-producing cells can produce long-term alleviation of behavioral seizures in an animal model.

Progress in Cell Grafting Therapy for Temporal Lobe Epilepsy

“…Bilateral grafting of conditionally immortalized neurons engineered to produce GABA into the substantia nigra of rats at 45 to 65 days after SE resulted in fewer SRS at 1 to 10 days postgrafting in comparison to the SE group that received only control cells [52], suggesting that grafting of cells that simply produce GABA can also diminish SRS if grafted into the seizure-modulating nucleus. Several other studies have also examined the effects of grafting of GABA-producing cells into the dentate gyrus or the substantia nigra on SRS in both kindling and SE models [53][54][55][56][57]. Transplantation of these cells were associated with increased GABA levels, enhanced local electrical seizure threshold, and delayed onset of behavioral SRS in the kindling model of epilepsy [53] and diminished extent of seizures in SE models [55,56].…”

“…Several other studies have also examined the effects of grafting of GABA-producing cells into the dentate gyrus or the substantia nigra on SRS in both kindling and SE models [53][54][55][56][57]. Transplantation of these cells were associated with increased GABA levels, enhanced local electrical seizure threshold, and delayed onset of behavioral SRS in the kindling model of epilepsy [53] and diminished extent of seizures in SE models [55,56].…”

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

“…This study was important for a number of reasons. First, it extended the anticonvulsant effect of transplanted cells from days to several weeks (reported in other studies 51,53,55 ) to several months to 1 year, by pretreatment of the tissue with growth factors and antiapoptotic agents. Second, it demonstrated that, in a model of SE that produces hippocampal and extrahippocampal damage (also seen in clinical cases of TLE 66 ), transplanting exclusively into the hippocampus could block seizure occurrence.…”

“…The use of clonal GABA-producing cell lines has provided a means to investigate transplant-induced seizuresuppression using a homogeneous population of GABAproducing cells 50,51,53,54,83 Clonal cell lines have been engineered using two main strategies: 1) GABA-producing neural cells have been immortalized with oncogenes, and these cells have also been additionally engineered with GAD 67 to make them GABA-overexpressing cell lines 50 , and 2) non-GABAergic neural cells have been immortalized 84 and then converted to a GABAergic phenotype by engineering the cells to express GAD 65 . 52 Although the transplantation of cells containing oncogenes (e.g., the SV40 large T oncogene) raises concerns about tumorigenicity, the use of genetically modified 85 or temperature-sensitive variants of the oncogene 52,78 (conditional immortalization) has largely avoided the problem of tumor formation.…”

“…Biochemical evaluation of the transplanted tissue in that study showed that GABA concentrations were elevated in the target tissue for the duration of the experiment. 51 Cells derived from genetically engineered neural cell lines provide a number of experimental advantages, but they also have limitations that diminish their clinical potential. Besides the concerns of tumorigenicity, and immunogenicity, a major problem has been an inability to sustain long-term effects due to the lack of survival or integration of cells derived from neuronal cell lines in the majority of studies.…”