Temporal changes of cytochrome P450 (Cyp) and eicosanoid-related gene expression in the rat brain after traumatic brain injury

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.

Effect of status epilepticus and antiepileptic drugs on CYP2E1 brain expression

“…The presented data and available evidences (Tindberg et al, 1996, Upadhya et al, 2001, Pardini et al, 2008, Hao et al, 2010, Mann et al, 2012, Zhong et al, 2012, Birnie et al, 2013) support the hypothesis of drug biotransformation in healthy and diseased brain ( e.g ., traumatic brain injury, ischemia, Alzheimer’s’ disease, epilepsy). Further studies are required to fully elucidate the functional relevance of selected P450 enzymes, such as CYP2E1, in the epileptic brain.…”

“…CYP2E1 expression was also augmented in astrocytes in response to pro-inflammatory factors (Tindberg et al, 1996). CYP2E1 transcripts are elevated in the rodent hippocampus following traumatic brain injury (Birnie et al, 2013). In addition, chronic consumption of drugs, including alcohol or nicotine, increased CYP2E1 brain levels and activity (Howard et al, 2003, Haorah et al, 2005).…”

“…Increasing evidence suggests CYP2E1 expression in rodent brain (Hansson et al, 1990). CYP2E1 was found in astrocytes, cerebral vessels and neurons in control animals and experimental models of ischemia or traumatic brain injury (Hansson et al, 1990, Tindberg et al, 1996, Birnie et al, 2013). …”

The role of biomarkers and MEG-based imaging markers in the diagnosis of post-traumatic stress disorder and blast-induced mild traumatic brain injury

“…Also metabolic functions can be altered after TBI. For example, changes in the cytochrome p450 superfamily of metabolic enzymes could influence the metabolism of inflammatory mediators, drugs and hormones (Birnie et al, 2013). Metabolic abnormalities have been proposed, but are yet to be studied in humans with PTSD (Naviaux, 2014).…”

“…Functional neuroimaging findings using positron emission topography (PET) and functional magnetic resonance imaging (fMRI) suggest that individuals with PTSD exhibit hyperresponsive amygdala activity to trauma or fear-related stimuli (for review, see Shin and Liberzon, 2010), during emotionally neutral tasks (Bryant et al, 2005;Shin et al, 2004b), and even at rest (Chung et al, 2006;Semple et al, 2000). A hyperresponsive amygdala contributes to the exaggerated fear response characteristic of PTSD (Anderson et al, 2003).…”