title: Neuroprotection of grafted neurons with a GDNF/caspase inhibitor cocktail.
abstract: Transplantation of fetal ventral mesencephalic (VM) tissue shows great promise as an experimental therapy for patients with Parkinson's disease. However, cell survival in brain tissue grafts is poor, with survival rates of only 5-15%. We have utilized a combination of the caspase inhibitor bocaspartyl (OMe)-fluoromethylketone (BOC-ASP-CH2F) and glial cell line-derived neurotrophic factor (GDNF) to enhance survival of grafted dopamine neurons. The VM tissue was dissected from embryonic day 13-15 rat fetuses, incubated in different doses of BOC-ASP-CH2F and GDNF, and transplanted to the anterior chamber of the eye of adult rats. Growth of the tissue was assessed through the translucent cornea. Doses of 50 and 100 micromolar of the general caspase inhibitor appeared to have detrimental effects on mesencephalic tissue, while 20 micromolar had beneficial effects on overall transplant growth. A combination of the caspase inhibitor and GDNF appeared to have more prominent effects on cell survival as well as dopaminergic fiber density than either agent by itself. The transplants doubled in size when they were treated with a combination of BOC-ASP-CH2F and GDNF, and cell death markers were significantly reduced at both 48 h and 4-6 days postgrafting. This is, to our knowledge, the first combined approach using apoptotic blockers with trophic factors, and demonstrates a viable strategy for protection of developing neurons, since several different aspects of graft function may be addressed simultaneously.
authors.affiliation: Department of Basic Science, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Helt
authors.forename: G R
authors.initials: GR
authors.lastname: Hoernig
authors.forename: D S
authors.initials: DS
authors.lastname: Albeck
authors.forename: G A
authors.initials: GA
authors.lastname: Gerhardt
authors.forename: B
authors.initials: B
authors.lastname: Ickes
authors.forename: M E
authors.initials: ME
authors.lastname: Reyland
authors.forename: D O
authors.initials: DO
authors.lastname: Quissell
authors.forename: I
authors.initials: I
authors.lastname: Strömberg
authors.forename: A C
authors.initials: AC
authors.lastname: Granholm
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016380:Brain Tissue Transplantation / Q000502:physiology*; D061945:Caspase Inhibitors; D004298:Dopamine / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016332:Fetal Tissue Transplantation / Q000502:physiology; D005333:Fetus; D005865:Gestational Age; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006085:Graft Survival / Q000187:drug effects* / Q000502:physiology; D020287:In Situ Nick-End Labeling; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D018696:Neuroprotective Agents; D051381:Rats; D011916:Rats, Inbred F344; D013378:Substantia Nigra / Q000166:cytology* / Q000637:transplantation*; D013997:Time Factors; D016042:Transplantation, Heterotopic; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
chemical_list: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C413643:benzyloxycarbonyl-aspartyl(O-methyl)fluoromethane; D001224:Aspartic Acid; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine