Rescue of ischemic brain injury by adenoviral gene transfer of glial cell line-derived neurotrophic factor after transient global ischemia in gerbils

Glial cell line-derived neurotrophic factor (GDNF), a member of the transfo rming growth factor (TGF)-beta superfamily, is one of the most potent neuro trophic factors and promotes survival of many populations of cells. We exam ined neuroprotective effect of an adenoviral vector encoding glial cell lin e-derived neurotrophic factor (AxCAhGDNF) on the transient global ischemia. Gerbils received administration of AxCAhGDNF or an adenoviral vector encod ing bacterial beta -galactosidase gene (AxCALacZ) through the lateral ventr icle. Two days later: occluding bilateral common carotid arteries for 5 min using aneurysm clips produced the transient global forebrain ischemia. Ani mals showed intense immunolabeling for GDNF in ependymal cells on 2, 4 and 7 days after the operation. The exogenous gene transducted by adenovirus in the same cells was detected by in situ hybridization. The treatment with A xCAhGDNF significantly prevented the loss of hippocampal CA1 pyramidal neur ons 2 to 7 days after the operation, as compared to AxCALacZ treatment. Als o terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick e nd labeling (TUNEL) staining was markedly reduced in the case with AxCAhGDN F treatment at 7 days after the operation. These results indicated that the adenovirus-mediated gene transfer of GDNF might prevent the delayed neuron al death of stroke and other disorders of the cerebral vasculature. (C) 200 0 Elsevier Science B.V. All rights reserved.