Pathophysiological Roles of Cyclooxygenases and Prostaglandins in the Central Nervous System

Cyclooxygenases (COXs) oxidize arachidonic acid to prostaglandin (PG) G(2) and H-2 followed by PG synthases that generates PGs and thromboxane (TX) A(2). COXs are divided into COX-1 and COX-2. In the central nervous system, COX-1 is constitutively expressed in neurons, astrocytes, and microglial cells. COX-2 is upregulated in these cells under pathophysiological conditions. In hippocampal long-term potentiation, COX-2, PGE synthase, and PGE(2) are induced in post-synaptic neurons. PGE(2) acts pre-synaptic EP2 receptor, generates cAMP, stimulates protein kinase A, modulates voltage-dependent calcium channel, facilitates glutamatergic synaptic transmission, and potentiates long-term plasticity. PGD(2), PGE(2), and PGI(2) exhibit neuroprotective effects via Gs-coupled DP1, EP2/EP4, and IP receptors, respectively. COX-2, PGD(2), PGE(2), PGF(2 alpha), and TXA(2) are elevated in stroke. COX-2 inhibitors exhibit neuroprotective effects in vivo and in vitro models of stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, and schizophrenia, suggesting neurotoxicities of COX products. PGE(2), PGF(2 alpha), and TXA(2) can contribute to the neurodegeneration via EP1, FP, and TP receptors, respectively, which are coupled with Gq, stimulate phospholipase C and cleave phosphatidylinositol diphosphate to produce inositol triphosphate and diacylglycerol. Inositol triphosphate binds to inositol triphosphate receptor in endoplasmic reticulum, releases calcium, and results in increasing intracellular calcium concentrations. Diacylglycerol activates calcium-dependent protein kinases. PGE(2) disrupts Ca2+ homeostasis by impairing Na+-Ca2+ exchange via EP1, resulting in the excess Ca2+ accumulation. Neither PGE(2), PGF(2 alpha), nor TXA(2) causes neuronal cell death by itself, suggesting that they might enhance the ischemia-induced neurodegeneration. Alternatively, PGE(2) is non-enzymatically dehydrated to a cyclopentenone PGA(2), which induces neuronal cell death. Although PGD(2) induces neuronal apoptosis after a lag time, neither DP1 nor DP2 is involved in the neurotoxicity. As well as PGE(2), PGD(2) is non-enzymatically dehydrated to a cyclopentenone 15-deoxy-Delta(12,14)-PGJ(2), which induces neuronal apoptosis without a lag time. However, neurotoxicities of these cyclopentenones are independent of their receptors. The COX-2 inhibitor inhibits both the anchorage-dependent and anchorage-independent growth of glioma cell lines regardless of COX-2 expression, suggesting that some COX-2-independent mechanisms underlie the antineoplastic effect of the inhibitor. PGE(2) attenuates this antineoplastic effect, suggesting that the predominant mechanism is COX-dependent. COX-2 or EP1 inhibitors show anti-neoplastic effects. Thus, our review presents evidences for pathophysiological roles of cyclooxygenases and prostaglandins in the central nervous system.