title: Enhanced prostacyclin synthesis by adenoviral gene transfer reduced glial activation and ameliorated dopaminergic dysfunction in hemiparkinsonian rats.
abstract: Prostacyclin (PGI2), a potent vasodilator and platelet antiaggregatory eicosanoid, is cytoprotective in cerebral circulation. It is synthesized from arachidonic acid (AA) by the sequential action of cyclooxygenase- (COX-) 1 or 2 and prostacyclin synthase (PGIS). Because prostacyclin is unstable in vivo, PGI2 analogs have been developed and demonstrated to protect against brain ischemia. This work attempts to selectively augment PGI2 synthesis in mixed glial culture or in a model of Parkinson's disease (PD) by direct adenoviral gene transfer of prostacyclin biosynthetic enzymes and examines whether it confers protection in cultures or in vivo. Confluent mixed glial cultures actively metabolized exogenous AA into PGE2 and PGD2. These PGs were largely NS398 sensitive and considered as COX-2 products. Gene transfer of AdPGIS to the cultures effectively shunted the AA catabolism to prostacyclin synthesis and concurrently reduced cell proliferation. Furthermore, PGIS overexpression significantly reduced LPS stimulation in cultures. In vivo, adenoviral gene transfer of bicistronic COX-1/PGIS to substantia nigra protected 6-OHDA- induced dopamine depletion and ameliorated behavioral deficits. Taken together, this study shows that enhanced prostacyclin synthesis reduced glial activation and ameliorated motor dysfunction in hemiparkinsonian rats. Prostacyclin may have a neuroprotective role in modulating the inflammatory response in degenerating nigra-striatal pathway.
authors.affiliation: Neural Regeneration Laboratory, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei 11221, Taiwan.
authors.forename: May-Jywan
authors.initials: MJ
authors.lastname: Tsai
authors.forename: Ching-Feng
authors.initials: CF
authors.lastname: Weng
authors.forename: Nien-Chu
authors.initials: NC
authors.lastname: Yu
authors.forename: Dann-Ying
authors.initials: DY
authors.lastname: Liou
authors.forename: Fu-San
authors.initials: FS
authors.lastname: Kuo
authors.forename: Ming-Chao
authors.initials: MC
authors.lastname: Huang
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Huang
authors.forename: Kabik
authors.initials: K
authors.lastname: Tam
authors.forename: Song-Kun
authors.initials: SK
authors.lastname: Shyue
authors.forename: Henrich
authors.initials: H
authors.lastname: Cheng
mesh_terms: D000256:Adenoviridae / Q000378:metabolism*; D000818:Animals; D001577:Benzophenones / Q000494:pharmacology; D002247:Carbon Isotopes; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D011464:Epoprostenol / Q000096:biosynthesis*; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008636:Mesencephalon / Q000473:pathology; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D016627:Oxidopamine; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014161:Transduction, Genetic
chemical_list: D001577:Benzophenones; C570822:CAY10449; D002247:Carbon Isotopes; D007093:Imidazoles; D008070:Lipopolysaccharides; D049452:Green Fluorescent Proteins; D009569:Nitric Oxide; D016627:Oxidopamine; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase