Anti-inflammatory effects of prostaglandin E2 in the central nervous system in response to brain injury and circulating lipopolysaccharide

Prostaglandin E-2 a product Of the cyclooxygenation of arachidonic acid released from membrane phospholipids, plays major roles in regulating brain injury and inflammation. Although prostaglandin E-2 has frequently been considered as a possible inducer of brain damage and degeneration, it may exert beneficial effects in the CNS. Indeed, in spite of its classic role as a pro-inflammatory molecule, several recent, in vitro observations indicate that prostaglandin E-2 can inhibit microglial activation. This study investigated the effect of central prostaglandin E-2 injection on circulating lipopolysaccharide-induced gene expression of different proinflammatory molecules in both vascular and parenchymal elements of the brain. Localized, but strong, expression of tumor necrosis factor-a and interleukin-1 beta mRNA was found at the edge of the intracerebroventricular tract, which was largely prevented by the central prostaglandin E-2 injection. Systemic lipopolysaccharide injection caused a profound transcriptional activation of cyclooxygenase-2 and the inhibitory factor kappaB alpha (1 kappaB alpha, index of NF-kappaB activity) in the cerebral endothelium and tumor necrosis factor-alpha in microglial cells across the brain parenchyma. Although exogenous prostaglandin E-2 increased lipopolysaccharide-induced NF-kappaB activity and cyclooxygenase-2 transcription in vascular-associated elements, it significantly reduced microglial activation and tumor necrosis factor-alpha expression in the brain parenchyma. These results indicate that prostaglandin E-2 may play an important role in modulating the immune response occurring at the injured site and the proinflammatory signaling events taking place in both vascular-and microglial-associated elements of the CNS.