P450 Eicosanoids and Reactive Oxygen Species Interplay in Brain Injury and Neuroprotection.

Significance: Eicosanoids are endogenous lipid mediators that play important roles in brain function and disease. Acute brain injury such as that which occurs in stroke and traumatic brain injury increases the formation of eicosanoids, which, in turn, exacerbate or diminish injury. In chronic neurodegenerative diseases such as Alzheimer's disease and vascular dementia (VD), eicosanoid synthetic and metabolizing enzymes are altered, disrupting the balance between neuroprotective and neurotoxic eicosanoids. Recent Advances: Human and experimental studies have established the opposing roles of hydroxy- and epoxyeicosanoids and their potential utility as diagnostic biomarkers and therapeutic targets in neural injury. Critical Issues: A gap in knowledge remains in understanding the cellular and molecular mechanisms underlying the neurovascular actions of specific eicosanoids, such as specific isomers of epoxyeicosatrienoic (EETs) and hydroxyeicosatetraenoic acids (HETEs). Future Directions: EETs and HETEs exert their actions on brain cells by targeting multiple mechanisms, which include surface G-protein coupled receptors. The identification of high-affinity receptors for EETs and HETEs and their cellular localization in the brain will be a breakthrough in our understanding of these eicosanoids as mediators of cell-cell communications and contributors to brain development, function, and disease. Antioxid. Redox Signal. 28, 987-1007.