Abstract
BackgroundTraumatic brain injury (TBI) induces arachidonic acid (ArA) release from cell membranes. ArA metabolites form a class of over 50 bioactive eicosanoids that can induce both adaptive and/or maladaptive brain responses. The dynamic metabolism of ArA to eicosanoids, and how they affect the injured brain, is poorly understood due to their diverse activities, trace levels, and short half-lives. The eicosanoids produced in the brain postinjury depend upon the enzymes present locally at any given time. Eicosanoids are synthesized by heme-containing enzymes, including cyclooxygenases, lipoxygenases, and arachidonate monoxygenases. The latter comprise a subset of the cytochrome P450 “Cyp” gene family that metabolize fatty acids, steroids, as well as endogenous and exogenous toxicants. However, for many of these genes neither baseline neuroanatomical nor injury-related temporal expression have been studied in the brain.In a rat model of parietal cortex TBI, Cyp and eicosanoid-related mRNA levels were determined at 6 h, 24 h, 3d, and 7d postinjury in parietal cortex and hippocampus, where dynamic changes in eicosanoids have been observed. Quantitative real-time polymerase chain reaction with low density arrays were used to assay 62 rat Cyps, 37 of which metabolize ArA or other unsaturated fatty acids; 16 eicosanoid-related enzymes that metabolize ArA or its metabolites; 8 eicosanoid receptors; 5 other inflammatory- and recovery-related genes, plus 2 mouse Cyps as negative controls and 3 highly expressed “housekeeping” genes.ResultsSixteen arachidonate monoxygenases, 17 eicosanoid-related genes, and 12 other Cyps were regulated in the brain postinjury (p < 0.05, Tukey HSD). Discrete tissue levels and distinct postinjury temporal patterns of gene expression were observed in hippocampus and parietal cortex.ConclusionsThe results suggest complex regulation of ArA and other lipid metabolism after TBI. Due to the temporal nature of brain injury-induced Cyp gene induction, manipulation of each gene (or its products) at a given time after TBI will be required to assess their contributions to secondary injury and/or recovery. Moreover, a better understanding of brain region localization and cell type-specific expression may be necessary to deduce the role of these eicosanoid-related genes in the healthy and injured brain.
Highlights
Traumatic brain injury (TBI) induces arachidonic acid (ArA) release from cell membranes
The conversion of arachidonic acid (ArA) to over 50 bioactive eicosanoids is catalyzed by a variety of enzymes including heme-containing cyclooxygenases, prostanoid synthases, lipoxygenases, and arachidonate monoxygenases
The latter, arachidonate hydroxylases and epoxygenases, comprise a subset of the cytochrome P450 or “Cyp” gene family of evolutionarily related proteins that metabolize polyunsaturated fatty acids, steroids, as well as endogenous and exogenous toxicant molecules in organisms from bacteria to primates [1]. These Cyp arachidonate monoxygenases produce hydroxyeicosatetraenoic acids and epoxyeicosatrienoic acids (HETEs and EETs) that modulate a variety of responses in the healthy and injured brain
Summary
Traumatic brain injury (TBI) induces arachidonic acid (ArA) release from cell membranes. The conversion of arachidonic acid (ArA) to over 50 bioactive eicosanoids is catalyzed by a variety of enzymes including heme-containing cyclooxygenases, prostanoid synthases, lipoxygenases, and arachidonate monoxygenases The latter, arachidonate hydroxylases and epoxygenases, comprise a subset of the cytochrome P450 or “Cyp” gene family of evolutionarily related proteins that metabolize polyunsaturated fatty acids, steroids, as well as endogenous and exogenous toxicant molecules in organisms from bacteria to primates [1]. These Cyp arachidonate monoxygenases produce hydroxyeicosatetraenoic acids and epoxyeicosatrienoic acids (HETEs and EETs) that modulate a variety of responses in the healthy and injured brain. EETs recently have been implicated in central nociceptive and hyperalgesic responses, with different EETs potentially moderating different effects on pain perception [22,30,31,32,33,34]
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