Cyclooxygenases in central nervous system diseases: a special role for cyclooxygenase 2 in neuronal cell death.

Abstract

I N THIS issueof theARCHIVES, SchwabandSchlueseneraddress the roles of cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2) in central nervous system (CNS) diseases and injury. First, they argue that COX-1 activity in CNS diseases has been overlooked. They point out that COX-1, although it is a constitutively expressed enzyme, accumulates under pathophysiologic conditions of chronic injury. Specifically, COX-1 is expressed in the microglia and macrophages that accumulate during recovery from hypoxicischemic or traumatic brain injury. It is also expressed in microglia and macrophages in Alzheimer disease. Second, Schwab and Schluesener also point out that our understanding of inflammation has recently been complicated by evidence suggesting that an initial proinflammatory burst of prostaglandin production can be followed by prostaglandin-mediated anti-inflammatory (reparative) responses. Evidence that COX-2 can play a role in the resolution of inflammation and wound healing in nonCNS tissues raises the possibility that COX-2 may have an as yet uncharacterized delayed reparative effect in CNS injury. Thus, Schwab and Schluesener argue that the emphasis on COX-2 as a pathogenic factor in CNS injury is misplaced. The hypothesis that COX-1 plays an important role in glial inflammation is well supported; both cyclooxygenase isoforms are expressed in activated glia. However, COX-2 is the predominant isoform within the neuron itself, has a special role in regulating synaptic activity, and contributes, at least in part, to neuronal death in a variety of disease states. Thus, we believe that the emphasis on COX-2 and the potential therapeutic use of selective COX-2 inhibitors in neurological diseases is well founded. Although the chemical properties of COX-2 and COX-1 are almost identical, COX-2 is expressed in different cellular and intracellular locations, and its expression is controlled by stimuli different than those for COX-1. The first-order product of both cyclooxygenase enzymes is prostaglandin H2, which is subsequently metabolized into prostaglandin D2, prostaglandin E2, prostaglandin F2 , prostacyclin, or thromboxane A2, depending on which specific prostaglandin synthases are expressed in that cell. Each of these first-order prostaglandins has specific receptors coupled to different second-messenger systems and biological responses. Thus, although COX-1 and COX-2 produce identical products, they are coupled to different physiologic responses utilizing different secondmessenger systems. The neuron is one cell type in whichCOX-2 ishighlyexpressed, and COX-2 may play a special role in normal neuronal function and in neuronal cell death. A special role of COX-2 within neurons was first elucidated by the studies of Yamagata et al, who cloned COX-2 from a rat seizure model. They found that COX-2 transcription is coupled to synaptic activity. Furthermore, N-methyl-Daspartate antagonists, such as MK801, block transcription of COX-2 induced by neuronal excitation, suggesting that COX-2 transcription is linked to increases in intracellular calcium. Consistent with this purported role in excitotoxic injury, COX-2 is expressed in the postsynaptic neuronal cell bodies of glutamatergic synapses. Interestingly, basal expression of COX-2 occurs primarily in the hippocampus and the limbic cortex, areas that are particularly vulnerable in hypoxicischemic injury and Alzheimer disease. COX-2 is also expressed in activated macrophages and in endothelial cells. Because inflammation isan importantphysiologiceffect ofcyclooxygenaseactivity, it is anatural assumption that activated macrophages and other inflammatory cells could mediate the pathologic effects of cyclooxygenase activity. In contrast, endothelial cell COX-2– dependent production of the potent vasodilator prostacyclin can increase blood flow and attenuate acute ischemic injury. Recent studies conclusively demonstrate that cyclooxygenase activity within the neuron itself can directly injure neurons independent of any effects on glial cells or blood flow. Hewett et al found that N-methylD-aspartate–induced cell injury could be ameliorated by treatment with selective COX-2 inhibitors. Li and Graham found that COX-2 inhibitors, From the Geriatric Research Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System (Dr Graham), and the Departments of Neurology (Dr Graham) and Pediatrics (Dr Hickey), University of Pittsburgh School of Medicine, Pittsburgh, Pa. SECTION EDITOR: STEVEN T. DEKOSKY, MD CONTROVERSIES IN NEUROLOGY