Many brain disorders such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Huntington, stroke, head trauma, and infection, are associated with inflammation that is involved in neuropathologenesis and hyperalgesis. Microglia and astrocytes act as immune cells in the inflamed brain. Both cell types, but especially microglia, are thought to contribute to the onset of inflammation in many brain diseases by producing deleterious proinflammatory mediators. Prostaglandins (PGs), which are critical mediators of physiologic processes and inflammation, are largely produced by activated microglia and reactive astrocytes during brain inflammation. These compounds are converted from arachnoidic acid (AA) by two isoforms of the cyclooxygenase (COX) enzyme, namely COX-1 and COX-2. In particular, the action of COX-2 and PGs in CNS inflammation has gained much attention recently. PGs have been found to act neuroprotectively by elevating intracellular cAMP levels in neurons. These molecules also function as anti-inflammatory molecules to reduce the production of nitric oxide and proinflammatory cytokines, and to increase the expression of anti-inflammatory cytokines. However, accumulating evidence also shows that COX inhibitors alleviate various types of brain damage via suppressing inflammatory reactions. Accordingly, the roles of two COX enzymes in mediating inflammation and anti-inflammation have recently been debated. We provide here a review of recent findings indicating that the reciprocal interaction of glial cell activation, COX enzymes and PGs mediates neurodegeneration and neuroprotection during brain inflammation. In addition, the mechanism by which PGs mediate signaling is discussed.

Astrocytes, the most abundant glia in the central nervous system (CNS), produce a large amount of prostaglandin E(2) (PGE(2)) in response to proinflammatory mediators after CNS injury. However, it is unclear whether PGE(2) has a regulatory role in astrocytic activity under the inflamed condition. In the present work, we showed that PGE(2) increased inducible nitric oxide synthase (iNOS) production by tumor necrosis factor-alpha and interferon-gamma (T/I) in astrocytes. Pharmacological and RNA interference approaches further indicated the involvement of the receptor EP2 in PGE(2)-induced iNOS upregulation in T/I-treated astrocytes. Quantitative real-time polymerase chain reaction and gel mobility shift assays also demonstrated that PGE(2) increased iNOS transcription through EP2-induced cAMP/protein kinase A (PKA)-dependent pathway. Consistently, the effect of EP2 was significantly attenuated by the PKA inhibitor KT-5720 and partially suppressed by the inhibitor (SB203580) of p38 mitogen-activated protein kinase (p38MAPK), which serves as one of the downstream components of the PKA-dependent pathway. Interestingly, EP2-mediated PKA signaling appeared to increase intracellular Ca(2+) release through inositol triphosphate (IP3) receptor activation, which might in turn stimulate protein kinase C (PKC) activation to promote iNOS production in T/I-primed astrocytes. By analyzing the expression of astrocytic glial fibrillary acidic protein (GFAP), we found that PGE(2) alone only triggered the EP2-induced cAMP/PKA/p38MAPK signaling pathway in astrocytes. Collectively, PGE(2) may enhance T/I-induced astrocytic activation by augmenting iNOS/NO production through EP2-mediated cross-talk between cAMP/PKA and IP3/Ca(2+) signaling pathways.

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