Prolonged Cyclooxygenase-2 Induction in Neurons and Glia Following Traumatic Brain Injury in the Rat

Abstract

Cyclooxygenase-2 (COX2) is a primary inflammatory mediator that converts arachidonic acid into precursors of vasoactive prostaglandins, producing reactive oxygen species in the process. Under normal conditions COX2 is not detectable, except at low abundance in the brain. This study demonstrates a distinctive pattern of COX2 increases in the brain over time following traumatic brain injury (TBI). Quantitative lysate ribonuclease protection assays indicate acute and sustained increases in COX2 mRNA in two rat models of TBI. In the lateral fluid percussion model, COX2 mRNA is significantly elevated (>twofold, p < 0.05, Dunnett) at 1 day postinjury in the injured cortex and bilaterally in the hippocampus, compared to sham-injured controls. In the lateral cortical impact model (LCI), COX2 mRNA peaks around 6 h postinjury in the ipsilateral cerebral cortex (fivefold induction, p < 0.05, Dunnett) and in the ipsilateral and contralateral hippocampus (two-and sixfold induction, respectively, p < 0.05, Dunnett). Increases are sustained out to 3 days postinjury in the injured cortex in both models. Further analyses use the LCI model to evaluate COX2 induction. Immunoblot analyses confirm increased levels of COX2 protein in the cortex and hippocampus. Profound increases in COX2 protein are observed in the cortex at 1-3 days, that return to sham levels by 7 days postinjury (p < 0.05, Dunnett). The cellular pattern of COX2 induction following TBI has been characterized using immunohistochemistry. COX2-immunoreactivity (-ir) rises acutely (cell numbers and intensity) and remains elevated for several days following TBI. Increases in COX2-ir colocalize with neurons (MAP2-ir) and glia (GFAP-ir). Increases in COX2-ir are observed in cerebral cortex and hippocampus, ipsilateral and contralateral to injury as early as 2 h postinjury. Neurons in the ipsilateral parietal, perirhinal and piriform cortex become intensely COX2-ir from 2 h to at least 3 days postinjury. In agreement with the mRNA and immunoblot results, COX2-ir appears greatest in the contralateral hippocampus. Hippocampal COX2-ir progresses from the pyramidal cell layer of the CA1 and CA2 region at 2 h, to the CA3 pyramidal cells and dentate polymorphic and granule cell layers by 24 h postinjury. These increases are distinct from those observed following inflammatory challenge, and correspond to brain areas previously identified with the neurological and cognitive deficits associated with TBI. While COX2 induction following TBI may result in selective beneficial responses, chronic COX2 production may contribute to free radical mediated cellular damage, vascular dysfunction, and alterations in cellular metabolism. These may cause secondary injuries to the brain that promote neuropathology and worsen behavioral outcome.

Inflammatory pain-induced signaling events following a conditional deletion of the N-methyl-d-aspartate receptor in spinal cord dorsal horn

“…In the absence of NMDA receptors, the CFA induced increased levels of glutamate in SCDH would likely bind to other glutamate receptors and/or glutamate transporters. Glutamate could induce neuronal COX-2 expression, as reported by Strauss and colleagues in cultured cerebellar granular cells (Strauss et al, 2000). In their report, glutamate-induced COX-2 expression is mediated by both NMDA and kainate receptors.…”

Hypoxia-Ischemia Induces DNA Synthesis without Cell Proliferation in Dying Neurons in Adult Rodent Brain

“…Adult rats were anesthetized by isoflurane and subjected to a unilateral piston impact while held in a stereotaxic apparatus (Strauss et al, 2000). The challenged rats were injected with BrdU (100 mg/kg) every 12 hr for 3 d and killed at 72 hr after injury for analysis (n ϭ 6).…”

A liquid chromatography/mass spectrometric method for simultaneous analysis of arachidonic acid and its endogenous eicosanoid metabolites prostaglandins, dihydroxyeicosatrienoic acids, hydroxyeicosatetraenoic acids, and epoxyeicosatrienoic acids in rat brain tissue

“…The physical insults of TBI set into motion a cascade of biochemical events that can result in secondary brain injury that is a major contributor to the ultimate tissue loss [4][5][6]. One part of this response is the increased conversion of AA to PGs as a result of induction of cyclooxygenase-2 (COX2) expression after TBI [7]. COX2 is one of the isoforms of COX and is highly induced by inflammatory stimuli [8,9].…”