Strategies for promoting anti-seizure effects of hippocampal fetal cells grafted into the hippocampus of rats exhibiting chronic temporal lobe epilepsy.
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abstract
Efficacy of hippocampal fetal cell (HFC) grafting for restraining spontaneous recurrent motor seizures (SRMS) in chronic temporal lobe epilepsy (TLE) is unknown. We investigated both survival and anti-seizure effects of 5'-bromodeoxyuridine (BrdU) labeled embryonic day 19 (E19) HFC grafts pretreated with different neurotrophic factors and a caspase inhibitor. Grafts were placed bilaterally into the hippocampi of F344 rats exhibiting kainate (KA) induced chronic TLE, where the frequency of SRMS varied from 3.0 to 3.5 seizures/8-h duration. The first group received standard (untreated) HFC grafts, the second group received HFC grafts pretreated and transplanted with brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and caspase inhibitor Ac-YVAD-cmk (BNC-treated HFC grafts), the third group received HFC grafts pretreated and transplanted with fibroblast growth factor-2 (FGF-2) and caspase inhibitor Ac-YVAD-cmk (FC-treated HFC grafts), and the fourth group served as epilepsy-only controls. Epileptic rats receiving standard HFC grafts exhibited 119% increase in the frequency of SRMS at 2 months post-grafting consistent with 125% increase in seizure frequency observed in epilepsy-only controls during the same period. However, in epileptic rats receiving HFC grafts treated with BNC or FC, the frequency of SRMS was 33-39% less than their pre-transplant scores and 73-76% less than rats receiving standard HFC grafts or epilepsy-only rats. The yield of surviving neurons was equivalent to 30% of injected cells in standard HFC grafts, 57% in HFC grafts treated with BNC and 98% in HFC grafts treated with FC. Thus, standard HFC grafts survive poorly in the chronically epileptic hippocampus and fail to restrain the progression of chronic TLE. In contrast, HFCs treated and grafted with BNC or FC survive robustly in the chronically epileptic hippocampus, considerably reduce the frequency of SRMS and blunt the progression of chronic TLE.
