Antiinflammatory and neuroprotective actions of COX2 inhibitors in the injured brain

Abstract

Overexpression of COX2 appears to be both a marker and an effector of neural damage after a variety of acquired brain injuries, and in natural or pathological aging of the brain. COX2 inhibitors may be neuroprotective in the brain by reducing prostanoid and free radical synthesis, or by directing arachidonic acid down alternate metabolic pathways. The arachidonic acid shunting hypothesis proposes that COX2 inhibitors' neuroprotective effects may be mediated by increased formation of potentially beneficial eicosanoids. Under conditions where COX2 activity is inhibited, arachidonic acid accumulates or is converted to eicosanoids via lipoxygenases and cytochrome P450 (CYP) epoxygenases. Several P450 eicosanoids have been demonstrated to have beneficial effects in the brain and/or periphery. We suspect that arachidonic acid shunting may be as important to functional recovery after brain injuries as altered prostanoid formation per se. Thus, COX2 inhibition and arachidonic acid shunting have therapeutic implications beyond the suppression of prostaglandin synthesis and free radical formation.

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 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).

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 inflammation, programmed cell death, free radical-mediated tissue damage, and alterations in cellular metabolism. These, in turn, cause secondary injuries that worsen clinical outcomes. Thus, COX2 inhibitors' beneficial actions are mediated both by reducing prostanoid formation and by arachidonic acid shunting to form antiinflammatory, neuroprotective eicosanoids.