Arachidonic acid metabolites: Function in neurotoxicity and inflammation in the central nervous system

Abstract

Arachidonic acid (AA) is liberated from membrane phospholipids by the action of phospholipases upon stimulation by a variety of extracellular stimuli including neurotransmitters, growth factors, and cytokines (Farooqui et al., 2006). As illustrated in Fig. 6.1, three enzyme systems act on AA to generate prostaglandin H2 via the cyclooxygenase enzymes (COX-1 and COX-2), leukotrienes via the LOX pathways, and epoxyeicosatrienoic acids via the epoxygenase cytochrome P450 pathway. These lipid products are signaling messengers and regulate a wide variety of physiologic functions including cerebral blood flow and synaptic function under basal conditions. Increases in expression and activity of enzymes in each of these three pathways have been documented in a wide spectrum of neurological diseases, including acute insults such as cerebral ischemia and trauma as well as chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Of the three enzymatic pathways, the cyclooxygenase (COX) pathway has been most studied, and a significant body of evidence links activity of this pathway and downstream prostanoid products to a broad range of neurological diseases. © 2008 Springer.