1998;95:10954C10959. beyond the suppression of prostaglandin synthesis and free radical formation. Introduction The role of cyclooxygenase-2 (COX2) and its inhibitors in the brain must be examined in the larger context of its role in arachidonic acid metabolism (Figure 1). Perturbations or insults to the brain activate phospholipases, releasing arachidonic acid from membrane stores (Dumuis et al., 1988; Gardiner et al., 1981). Cyclooxygenase-2 catalyzes the conversion of arachidonic acid and molecular oxygen into vasoactive prostaglandins, producing reactive oxygen free radicals in the process. COX2 is the dominant player in a complex and interlocking metabolic pathway that converts a structural membrane lipid into a plethora of biologically active eicosanoids, many of which have opposing physiological activity. Moreover, there are several other related biomolecules (e.g., docosahexenoic acid and docosanoids, the endocannabinoids anandamide and 2-arachidonoyl glycerol, etc.) that further expand the scope of influence of COX2 in neurophysiological functions. Open in a separate window Figure 1 Arachidonic acid metabolism. Cell damage and phospholipase activation release arachidonic acid with subsequent oxidation to a variety of eicosanoids. Arachidonic acid is converted to highly labile prostanoids and leukotrienes by COXs and lipoxygenases, respectively, producing reactive oxygen free radicals in the process. Alternatively, arachidonic acid can be monooxygenated by cytochrome P450 epoxygenases, producing highly labile epoxide regioisomers (5,6-; 8,9-; 11,12-; or 14,15-EET)(Chacos et al., 1982; Oliw et al., 1982). Allylic oxidation is also Rabbit Polyclonal to Cortactin (phospho-Tyr466) catalyzed to form HETEs (5-, 8-, 9-, 11-, 12-, 15-, 19-, or M344 20-HETE)(Capdevila et al., 1982; Oliw et al., 1982). Certain HETEs (e.g., 5-, or 12-HETE) can also be formed via lipoxygenase action from hydroperoxyeicosatetraenoic acid (HPETE) precursors. EETs are metabolized by epoxide hydrolase to the corresponding dihydroxyeicosatrienoic acids (DHETs)(Chacos et al., 1983; Oliw et al., 1982; Yu et al., 2000b; Zeldin et al., 1995). Interestingly, EETs and HETEs are often incorporated in membrane phospholipid, enabling phospholipase-mediated release of these activities (Brezinski and Serhan, 1990; Capdevila et al., 1987; Karara et al., 1991). Inhibition of COX2 after pathological insult has been shown to benefit recovery in the brain and spinal cord (Nagayama et al., 1999; Resnick et al., 1998). However, the mechanisms of COX2 in neuropathology are not well described. Our working hypothesis is that COX2 expression in the brain interferes with intrinsic neuroprotective mechanisms, contributing to the establishment of a vicious cycle in which cell death, rather than survival pathways dominate; and tissue damage is made worse by propagation of oxidative damage and chemotactic signals. Thus, we propose that COX2 inhibition blocks delayed cell death and neuroinflammation. That COX2 inhibitors may function in the brain by shunting arachidonic acid down alternate metabolic pathways has been alluded to M344 by Christie et al. (Christie et al., 1999) in a model of opioid-NSAID synergy, who speculated that blockade of cyclooxygenase and/or 5-lipoxygenase might lead to shunting of arachidonic acid metabolism [and] enhanced formation of 12-LOX metabolites, thereby enhancing the efficacy of opioids in the periaqueductal gray. Arachidonic acid can be oxidized to many biologically and chemically active derivatives, the most prevalent being prostaglandins. Thus, under conditions where COX2 activity increases, proportionately more arachidonic acid is converted to prostanoids and less to other metabolites. Conversely, when COX2 activity is inhibited, arachidonic acid, that would otherwise be converted to prostanoids, accumulates or is converted to other eicosanoids (Figure 2, arachidonic acid shunting). Both these conditions are especially germane under conditions where phospholipases are activated, with the resultant increase in free arachidonic acid. The succeeding review examines some observations of the reactions of COX2 to brain injuries, its association with cell death and neuroinflammation, and its response to COX2 inhibitor treatments. Open in a separate M344 window Figure 2 Arachidonic acid shunting. The action of COX2 inhibitors decreases synthesis of prostanoids and free radicals. However, because it is the dominant metabolic reaction, COX2 inhibition causes arachidonic acid shunting down alternate enzymatic pathways (e.g., cytochrome P450 epoxygenases), resulting in the synthesis of potentially neuroprotective eicosanoids. COX2 and prostanoid levels rise acutely after brain injuries, and remain elevated for days. The extent of COX2 expression may correlate to the severity of the insult. This may be due to a vicious cycle, in which secondary injury cascades promulgate COX2 gene expression. Prolonged elevation contributes to.Soc Neurosci Abs. have therapeutic implications beyond the suppression of prostaglandin synthesis and free radical formation. Introduction The role of cyclooxygenase-2 (COX2) and its inhibitors in the brain must be examined in the larger context of its role in arachidonic acid metabolism (Figure 1). Perturbations or insults to the brain activate phospholipases, releasing arachidonic acid from M344 membrane stores (Dumuis et al., 1988; Gardiner et al., 1981). Cyclooxygenase-2 catalyzes the conversion of arachidonic acid and molecular oxygen into vasoactive prostaglandins, producing reactive oxygen free radicals in the process. COX2 is the dominant player in a complex and interlocking metabolic pathway that converts a structural membrane lipid into a plethora of biologically active eicosanoids, many of which have opposing physiological activity. Moreover, there are several other related biomolecules (e.g., docosahexenoic acid and docosanoids, the endocannabinoids anandamide and 2-arachidonoyl glycerol, etc.) that further expand the scope of influence of COX2 in neurophysiological functions. Open in a separate window Figure 1 Arachidonic acid metabolism. Cell damage and phospholipase activation release arachidonic acid with subsequent oxidation to a variety of eicosanoids. Arachidonic acid is converted to highly labile prostanoids and leukotrienes by COXs and lipoxygenases, respectively, producing reactive oxygen free radicals in the process. Alternatively, arachidonic M344 acid can be monooxygenated by cytochrome P450 epoxygenases, producing highly labile epoxide regioisomers (5,6-; 8,9-; 11,12-; or 14,15-EET)(Chacos et al., 1982; Oliw et al., 1982). Allylic oxidation is also catalyzed to form HETEs (5-, 8-, 9-, 11-, 12-, 15-, 19-, or 20-HETE)(Capdevila et al., 1982; Oliw et al., 1982). Certain HETEs (e.g., 5-, or 12-HETE) can also be formed via lipoxygenase action from hydroperoxyeicosatetraenoic acid (HPETE) precursors. EETs are metabolized by epoxide hydrolase to the corresponding dihydroxyeicosatrienoic acids (DHETs)(Chacos et al., 1983; Oliw et al., 1982; Yu et al., 2000b; Zeldin et al., 1995). Interestingly, EETs and HETEs are often incorporated in membrane phospholipid, enabling phospholipase-mediated release of these activities (Brezinski and Serhan, 1990; Capdevila et al., 1987; Karara et al., 1991). Inhibition of COX2 after pathological insult has been shown to benefit recovery in the brain and spinal cord (Nagayama et al., 1999; Resnick et al., 1998). However, the mechanisms of COX2 in neuropathology are not well described. Our working hypothesis is that COX2 expression in the brain interferes with intrinsic neuroprotective mechanisms, contributing to the establishment of a vicious cycle in which cell death, rather than survival pathways dominate; and tissue damage is made worse by propagation of oxidative damage and chemotactic signals. Thus, we propose that COX2 inhibition blocks delayed cell death and neuroinflammation. That COX2 inhibitors may function in the brain by shunting arachidonic acid down alternate metabolic pathways has been alluded to by Christie et al. (Christie et al., 1999) in a model of opioid-NSAID synergy, who speculated that blockade of cyclooxygenase and/or 5-lipoxygenase might lead to shunting of arachidonic acid metabolism [and] enhanced formation of 12-LOX metabolites, thereby enhancing the efficacy of opioids in the periaqueductal gray. Arachidonic acid can be oxidized to many biologically and chemically active derivatives, the most prevalent being prostaglandins. Thus, under conditions where COX2 activity increases, proportionately more arachidonic acid is converted to prostanoids and much less to various other metabolites. Conversely, when COX2 activity is normally inhibited, arachidonic acidity, that would usually be changed into prostanoids, accumulates or is normally converted to various other eicosanoids (Amount 2, arachidonic acidity shunting). Both these circumstances are specially germane under circumstances where phospholipases are turned on, using the resultant upsurge in free of charge arachidonic acidity. The being successful review examines some observations.