Abstract
BackgroundNeuroinflammation contributes to the pathophysiology of acute CNS injury, including traumatic brain injury (TBI). Although prostaglandin lipid mediators of inflammation contribute to a variety of inflammatory responses, their importance in neuroinflammation is not clear. There are conflicting reports as to the efficacy of inhibiting the enzymes required for prostaglandin formation, cyclooxygenase (COX) -1 and COX-2, for improving outcomes following TBI. The purpose of the current study was to determine the role of the COX isoforms in contributing to pathological processes resulting from TBI by utilizing mice deficient in COX-1 or COX-2.ResultsFollowing a mild controlled cortical impact injury, the amount of cortical tissue loss, the level of microglial activation, and the capacity for functional recovery was compared between COX-1-deficient mice or COX-2-deficient mice, and their matching wild-type controls. The deficiency of COX-2 resulted in a minor (6%), although statistically significant, increase in the sparing of cortical tissue following TBI. The deficiency of COX-1 resulted in no detectable effect on cortical tissue loss following TBI. As determined by 3[H]-PK11195 autoradiography, TBI produced a similar increase in microglial activation in multiple brain regions of both COX-1 wild-type and COX-1-deficient mice. In COX-2 wild-type and COX-2-deficient mice, TBI increased 3[H]-PK11195 binding in all brain regions that were analyzed. Following injury, 3[H]-PK11195 binding in the dentate gyrus and CA1 region of the hippocampus was greater in COX-2-deficient mice, as compared to COX-2 wild-type mice. Cognitive assessment was performed in the wild-type, COX-1-deficient and COX-2-deficient mice following 4 days of recovery from TBI. There was no significant cognitive effect that resulted from the deficiency of either COX-1 or COX-2, as determined by acquisition and spatial memory retention testing in a Morris water maze.ConclusionThese findings suggest that the deficiency of neither COX-1 nor COX-2 is sufficient to alter cognitive outcomes following TBI in mice.
Highlights
Neuroinflammation contributes to the pathophysiology of acute CNS injury, including traumatic brain injury (TBI)
Analysis of the pre-injury performance of the COX-2 +/+ and COX-2 -/- animals revealed a significant day effect [F(3,51) = 0.81, p < 0.0001] that followed a similar pattern as described for the COX-1 animals (Figure 1B), where there were no differences between the abilities of the wild-type and null mutant mice to learn the location of the platform before injury
Post-Injury Cognitive Assessment Following TBI, average latency increased from 14.18 ± 5.29 sec and 9.6 ± 3.54 sec, for COX-1 +/+ and -/- animals, respectively, to 26.44 ± 11.06 sec and 25.97 ± 10.76 sec, suggesting that Cortical Impact (CCI) impaired the ability of these animals to remember the location of the submerged platform
Summary
Neuroinflammation contributes to the pathophysiology of acute CNS injury, including traumatic brain injury (TBI). The increased accumulation of COX-1 expressing microglia has been identified in other types of CNS injury, including ischemic injury [4,5], and pharmacological inhibition of COX-1 has been shown to be effective in reducing neuronal damage following ischemia [6]. These studies showing increased expression and a potential causative role for COX-1 have suggested that COX-1 inhibition may provide a more effective therapy for TBI than inhibition of COX-2 [2]
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