Prostaglandin E2 EP1 receptors:downstream effectors of COX-2 neurotoxicity

Nat med. 12:225-9, 2006

Speaker:洪惠雯                         Date: 2006 /4/19

Commentator:黃朝慶  醫師              Time:15:10~16:00  Room:601

Abstract:

Prostaglandin endoperoxide synthase, commonly called cyclooxygenase (COX), is the key enzyme for the conversion of arachidonic acid to prostaglandins. The two known COX isoforms are referred to as COX-1 and COX-2. In many situations, the COX-1 enzyme is produced constitutively, whereas COX-2 is highly inducible. In the brain, COX-2 is expressed in discrete populations of neurons, is enriched in the cortex and hippocampus, and has been implicated in brain functions and in neurologic disorders, including stroke, seizures, and Alzheimer’s disease, which COX-2 is markedly upregulated, and its reaction products have critical roles in a wide variety of pathologies associated with glutamate excitotoxicity. Moreover, prostaglandin E2 (PGE2) regulates synaptic transmission and plasticity through PGE2 receptors (EPs). Therefore, the authors investigated the role of PGE2 EP1 receptors in hypoxic ischemia brain injury and in the neurotoxicity of COX-2. They found that COX-2-derived PGE2 contributed to N-methy-D-aspartate (NMDA) neurotoxicity through activation of EP1 receptors. Thus, their study provide a previously unrecongnized link between EP1 receptors and the regulation of Na⁺-Ca²⁺ exchange, a process critical for neuronal survival. Consequently, inhibition of EP1 receptors provides the pharmaceutical target to block the after effect of COX-2 without compromising the beneficial effects of COX-2 activity.

Reference:

1. Kawano T et al. (2006) Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity. Nat Med. 12:225-9.

2. Sattler R, Tymianski M.(2001) Molecular mechanisms of glutamate receptor-mediated excitotoxic neuronal cell death. Mol Neurobiol. 24:107-29.

3. FitzGerald GA. (2003) COX-2 and beyond: Approaches to prostaglandin inhibition in human disease. Nat Rev Drug Discov. 2:879-90.