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 achieved increasing interest in the treatment of neurodegenerative diseases. However, gene therapy requires that delivered genes are translated into proteins. This may pose a problem in focal ischemia where protein synthesis is compromized. The present study was conducted to find out the feasibility of adenoviral GDNF and CNTF delivery in transient focal ischemia, as induced by 30 min of intraluminar middle cerebral artery (MCA) occlusion in mice. Injections of vehicle, of an adenoviral vector deleted in the E1 region (Ad-dE1) and of vectors expressing the GDNF (Ad-GDNF), CNTF (Ad-CNTF), or GFP (Ad-EGFP) gene from a CMV promoter were stereotactically placed in the dorsolateral striatum, i.e., the core of the MCA territory, and focal ischemia was induced seven days later. Thread occlusion resulted in disseminated injury of the striatum, but not the overlying cortex. The number of viable neurons was significantly increased after 1 and 3 days of reperfusion both in Ad-GDNF 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 violet staining, terminal transferase biotinylated-dUTP nick end-labeling (TUNEL), and immunocytochemistry for activated caspase-3. Interestingly, the protective effects of Ad-GDNF were similarly strong in areas of the striatum adjacent and remote of the adenoviral infusion site, while Ad-CNTF showed pronounced rescue effects in the surrounding, but rather little effects distant to the infusion. The present study demonstrates that adenoviral delivery of neurotrophic factors may be a useful tool for the treatment of focal ischemia.
Hermann
D M
DM
Department of Neurology, University of Tübingen, Hoppe-Seyler-Strasse 3, D-72076 Tübingen, Germany.
Kilic
E
E
Kügler
S
S
Isenmann
S
S
Bähr
M
M
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001253:Astrocytes / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002560:Cerebrovascular Circulation; D020934:Ciliary Neurotrophic Factor / Q000235:genetics*; D003342:Corpus Striatum / Q000098:blood supply / Q000473:pathology*; D015870:Gene Expression; D015316:Genetic Therapy; D051100:Glial Cell Line-Derived Neurotrophic Factor; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000628:therapy; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000628:therapy*; D017078:Laser-Doppler Flowmetry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000473:pathology; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents
D020934:Ciliary Neurotrophic Factor; C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases