Grafting of striatal precursor cells into hippocampus shortly after status epilepticus restrains chronic temporal lobe epilepsy.
Status epilepticus (SE) typically progresses into temporal lobe epilepsy (TLE) typified by complex partial seizures. Because sizable fraction of patients with TLE exhibit chronic seizures that are resistant to antiepileptic drugs, alternative therapies that are efficient for diminishing SE-induced chronic epilepsy have great significance. We hypothesize that bilateral grafting of appropriately treated striatal precursor cells into hippocampi shortly after SE is efficacious for diminishing SE-induced chronic epilepsy through long-term survival and differentiation into GABA-ergic neurons. We induced SE in adult rats via graded intraperitoneal injections of kainic acid, bilaterally placed grafts of striatal precursors (pre-treated with fibroblast growth factor-2 and caspase inhibitor) into hippocampi at 4 days post-SE, and examined long-term effects of grafting on spontaneous recurrent motor seizures (SRMS). Analyses at 9-12 months post-grafting revealed that, the overall frequency of SRMS was 67-89% less than that observed in SE-rats that underwent sham-grafting surgery and epilepsy-only controls. Graft cell survival was approximately 33% of injected cells and approximately 69% of surviving cells differentiated into GABA-ergic neurons, which comprised subclasses expressing calbindin, parvalbumin, calretinin and neuropeptide Y. Grafting considerably preserved hippocampal calbindin but had no effects on aberrant mossy fiber sprouting. The results provide novel evidence that bilateral grafting of appropriately treated striatal precursor cells into hippocampi shortly after SE is proficient for greatly reducing the frequency of SRMS on a long-term basis in the chronic epilepsy period. Presence of a large number of GABA-ergic neurons in grafts further suggests that strengthening of the inhibitory control in host hippocampi likely underlies the beneficial effects mediated by grafts.
Hattiangady
Bharathi
B
Department of Surgery (Neurosurgery) Duke University Medical Center, Durham, NC 27710, USA.
Rao
Muddanna S
MS
Shetty
Ashok K
AK
D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004622:Embryo, Mammalian; D004833:Epilepsy, Temporal Lobe / Q000209:etiology / Q000601:surgery*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006624:Hippocampus / Q000601:surgery*; D007608:Kainic Acid; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000145:classification / Q000378:metabolism; D009478:Neuropeptide Y / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013226:Status Epilepticus / Q000139:chemically induced / Q000150:complications; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
D009419:Nerve Tissue Proteins; D009478:Neuropeptide Y; D016222:Fibroblast Growth Factor 2; D001973:Bromodeoxyuridine; D007608:Kainic Acid