title: Combined neurotrophic supplementation and caspase inhibition enhances survival of fetal hippocampal CA3 cell grafts in lesioned CA3 region of the aging hippocampus.
abstract: Fetal hippocampal CA3 cells show excellent survival when homotopically grafted into the kainic acid-lesioned CA3 region of the young adult hippocampus, a model of temporal lobe epilepsy. However, survival of these cells in the kainic acid-lesioned CA3 region of the aging hippocampus is unknown. We hypothesize that fetal CA3 grafts into the lesioned CA3 region of the middle-aged and aged hippocampus exhibit significantly diminished cell survival compared with similar grafts in the lesioned young adult hippocampus unless pre-treated and transplanted with factors that augment graft cell survival. We analyzed cell survival of 5'-bromodeoxyuridine-labeled embryonic day 19 CA3 grafts following their transplantation into the lesioned CA3 region of the middle-aged and aged rat hippocampus. Grafts were placed 4 days after an i.c.v. administration of kainic acid, and absolute cell survival of grafts was quantified 1 month after grafting using 5'-bromodeoxyuridine immunostaining of serial sections and the optical fractionator counting method. Grafts into both middle-aged and aged hippocampus exhibited analogous but significantly diminished cell survival (30% of injected cells) compared with similar grafts into the young adult hippocampus (72% cell survival). However, the extent of cell survival of CA3 grafts pre-treated and transplanted with a combination of neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 and the caspase inhibitor acetyl-tyrosinyl-valyl-alanyl-aspartyl-chloro-methylketone was significantly enhanced in both middle-aged and aged hippocampus (51-63% cell survival). These results underscore that aging impairs the conduciveness of the CA3 region for robust survival of homotopic fetal CA3 grafts after lesion. However, a combined neurotrophic supplementation and caspase inhibition significantly enhances survival of fetal CA3 cells in the lesioned aging hippocampus. Thus, pre-treatment and grafting of donor cells with a combination of factors that support growth of specific donor cells may considerably enhance survival and integration of fetal grafts into the lesioned aging CNS in clinical trials.
authors.affiliation: Medical Research Service, Veterans Affairs Medical Center, Durham, NC 27705, USA.
authors.forename: V
authors.initials: V
authors.lastname: Zaman
authors.forename: A K
authors.initials: AK
authors.lastname: Shetty
mesh_terms: D000375:Aging / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D016380:Brain Tissue Transplantation / Q000379:methods*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000473:pathology* / Q000601:surgery; D005260:Female; D005333:Fetus; D006085:Graft Survival / Q000187:drug effects* / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000601:surgery / Q000637:transplantation*; D007150:Immunohistochemistry; D008297:Male; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000637:transplantation*; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D061945:Caspase Inhibitors; D009414:Nerve Growth Factors; D020169:Caspases