Adenovirus-mediated GDNF and CNTF pretreatment protects against striatal injury following transient middle cerebral artery occlusion in mice

During the last few years, adenoviral gene transfer techniques have achieve d increasing interest in the treatment of neurodegenerative diseases. Howev er, gene therapy requires that delivered genes are translated into proteins . This may pose a problem in focal ischemia where protein synthesis is comp romized. The present study was conducted to find out the feasibility of ade noviral GDNF and CNTF delivery in transient focal ischemia, as induced by 3 0 min of intraluminar middle cerebral artery (MCA) occlusion in mice. Injec tions of vehicle, of an adenoviral vector deleted in the El region (Ad-dE1) and of vectors expressing the GDNF (Ad-GDNF), CNTF (Ad-CNTF), or GFP (Ad-E GFP) gene from a CMV promoter were stereotactically placed in the dorsolate ral striatum, i.e., the core of the MCA territory, and focal ischemia was i nduced seven days later. Thread occlusion resulted in disseminated injury o f the striatum, but not the overlying cortex. The number of viable neurons was significantly increased after I and 3 days of reperfusion both in Ad-GD NF and Ad-CNTF as compared with vehicle or Ad-dE1-treated animals, whereas the number of injured cells was significantly reduced, as shown by cresyl v iolet staining, terminal transferase biotinylated-dUTP nick end-labeling (T UNEL), and immunocytochemistry for activated caspase-3. Interestingly, the protective effects of Ad-GDNF were similarly strong in areas of the striatu m adjacent and remote of the adenoviral infusion site, while Ad-CNTF showed pronounced rescue effects in the surrounding, but rather little effects di stant to the infusion. The present study demonstrates that adenoviral deliv ery of neurotrophic factors may be a useful tool for the treatment of focal ischemia. (C) 2001 Academic Press.