Cyclooxygenase-1 and bicistronic cyclooxygenase-1/prostacyclin synthase gene transfer protect against ischemic cerebral infarction.
BACKGROUND
We tested the hypothesis that bicistronic cyclooxygenase-1 (COX-1)/prostacyclin synthase (PGIS) and COX-1 gene transfer reduce cerebral infarct volume by augmenting synthesis of protective prostaglandins.


RESULTS
We infused into lateral ventricle of a rat stroke model recombinant adenoviruses (rAd) containing COX-1 (Adv-COX-1), COX-1 and PGIS (Adv-COX-1/PGIS), or Adv-PGK control vector, and we determined COX-1 and PGIS protein and eicosanoid levels and infarct volume. COX-1 and PGIS proteins were increased in a time-dependent manner. Adv-COX-1/PGIS infusion selectively augmented prostacyclin levels, with reduction of other eicosanoids in ischemic cortex and a significant reduction of infarct volume, even when the rAd was administered 5 hours after ischemia. Infusion of Adv-COX-1 also increased prostacyclin, suppressed leukotriene levels, and achieved a similar degree of cerebral protection. Its neuroprotection was abrogated by treatment with a selective COX-1 inhibitor.


CONCLUSIONS
COX-1/PGIS and COX-1 gene transfer reduce cerebral infarct volume by augmenting prostacyclin and suppressing leukotriene productions. COX-1-based gene transfer has potential for treating ischemic stroke.
Lin
Heng
H
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Lin
Teng-Nan
TN
Cheung
Wai-Mui
WM
Nian
Gau-Ming
GM
Tseng
Ping-Hui
PH
Chen
Shu-Fen
SF
Chen
Jean-Ju
JJ
Shyue
Song-Kun
SK
Liou
Jun-Yang
JY
Wu
Cheng-Wen
CW
Wu
Kenneth K
KK
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism; D002545:Brain Ischemia / Q000628:therapy; D002544:Cerebral Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051545:Cyclooxygenase 1; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D011464:Epoprostenol / Q000096:biosynthesis; D005796:Genes; D015316:Genetic Therapy; D005822:Genetic Vectors; D006352:Heart Ventricles; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis / Q000235:genetics*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins; D018696:Neuroprotective Agents / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics*; D011453:Prostaglandins / Q000096:biosynthesis; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans
D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D011453:Prostaglandins; D011720:Pyrazoles; C115461:SC 560; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D051545:Cyclooxygenase 1; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase