Adenovirus-mediated glial cell line-derived neurotrophic factor (GDNF) expression protects against subsequent cortical cold injury in rats.
We examined whether brain damage after focal cortex trauma may be attenuated by adenoviral delivery of the glial cell line-derived neurotrophic factor (GDNF) gene. For this reason, injections of vehicle, of an adenoviral vector deleted in the E1 region (Ad-dE1) or a vector expressing the GDNF gene from a CMV promoter (Ad-GDNF) were stereotactically placed in the rat sensorimotor cortex, and one day later cold lesions of the cerebral cortex were induced. Lesions were associated with pronounced brain swelling one day after injury. The degree of brain swelling was significantly attenuated by Ad-GDNF delivery (Ad-GDNF: 7.4 +/- 2.2%, Ad-dE1: 21.1 +/- 4.9%, vehicle: 20.9 +/- 5.0% of contralateral; mean +/- SEM, P < 0.05). Furthermore, Ad-GDNF treatment resulted in a significant reduction of the lesion volume seven days after lesioning (Ad-GDNF: 21.8 +/- 2.8 mm3, Ad-dE1: 44.1 +/- 1.6 mm3, vehicle 40.9 +/- 8.6 mm3, P < 0.05). The decrease in the lesion size was associated with a reduction in the number of inducible nitric oxide (iNOS)(+), activated caspase-3(+) and DNA fragmented cells in the perilesion rim, as revealed by immunocytochemistry and terminal transferase biotinylated-dUTP nick end labeling (TUNEL). In Ad-GDNF-treated animals, the number of caspase-3(+) and TUNEL(+) cells was also reduced in the lesion-remote thalamus. The present study shows that adenoviral GDNF delivery is protective in focal cortex trauma.
Hermann
D M
DM
Department of Neurology, University of Tübingen, Hoppe-Seyler-Strasse 3, Tübingen, D-72076, Germany.
Kilic
E
E
Kügler
S
S
Isenmann
S
S
Bähr
M
M
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001929:Brain Edema / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002540:Cerebral Cortex / Q000293:injuries* / Q000378:metabolism / Q000821:virology; D002544:Cerebral Infarction / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D003080:Cold Temperature / Q000009:adverse effects; D053938:DNA Fragmentation / Q000502:physiology; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D051100:Glial Cell Line-Derived Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D017628:Microglia / Q000166:cytology / Q000378:metabolism; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000378:metabolism / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D019001:Nitric Oxide Synthase; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases