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.

Prostaglandin I2 Attenuates Prostaglandin E2-Stimulated Expression of Interferon γ in a β-Amyloid Protein- and NF-κB-Dependent Mechanism

“…Although there is no direct evidence that supports our data, PGE 2 treatment stimulates the activity of cultured astrocytes by elevating the levels of GFAP 54 . In contrast, PGI 2 suppresses the activity of astrocytes by reducing the expression of GFAP 55 56 . The trends of astrocytes activity were similar to that of IFNγ expression.…”

Hippocampal neuronal cyclooxygenase-2 downstream signaling imbalance in a rat model of chronic aluminium gluconate administration

“…Cerebral ischemia reperfusion insult will cause a delayed and transient induction of PGIS in hippocampus and cortex neurons [ 30 ]. COX-1/PGIS adenoviral gene transfer to substantia nigra will prevent dopamine depletion and behavioral deficits induced by 6-OHDA in rats [ 53 ]. The infarct volume and behavioral damage in IP−/−mice were significantly enhanced compared with the wild-type mice, and administration of beraprost, a selective IP agonist, significantly improved the neurological deficit and decreased the infarct volume in wild-type mice [ 54 ].…”

Beraprost sodium protects against chronic brain injury in aluminum-overload rats

“…Cerebral ischemia reperfusion injury will result in a delayed and transient induction of PGIS in cortex and hippocampus neurons [ 19 ]. COX-1/PGIS adenoviral gene transfer to substantia nigra can prevent 6-OHDA-induced dopamine depletion and behavioral deficits in rats [ 20 ]. Combined gene transfer of COX-1 and PGIS also can increase PGI2 level and reduce cerebral infarct volume [ 12 ].…”