Celecoxib in a Preclinical Model of Repetitive Mild Traumatic Brain Injury: Hippocampal Learning Deficits Persist with Inflammatory and Excitotoxic Neuroprotection

Matthew Hiskens,Rebecca Vella,Andrew Fenning,Anthony Schneiders

doi:10.3390/traumacare1010003

Matthew Hiskens, Rebecca Vella + Show 2 more

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https://doi.org/10.3390/traumacare1010003

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Abstract

Repetitive mild traumatic brain injuries (mTBIs) contribute to inflammation-induced neurodegeneration. Cycloxygenase (COX) enzymes produce inflammatory cytokines that influence the microglia response to neurotrauma. Celecoxib is a selective COX-2 inhibitor that is prescribed in some conditions of mTBI to alleviate symptoms of concussion, and has shown benefits in neurodegenerative conditions. We investigated molecular pathways of neuroinflammation in response to celecoxib treatment in a mouse model of repetetive mTBI. Fifteen mTBIs were delivered over 23 days in adult male C57BL/6J mice in one of four groups (control, celecoxib without impact, celecoxib with impact, and vehicle with impact). Cognitive function was assessed at 48 h and three months following the final mTBI. Morris Water Maze testing revealed impaired hippocampal spatial learning performance in the celecoxib treatment with the impact group compared to the vehicle with impact control in the acute phase, with celecoxib treatment providing no improvement compared with the control at chronic testing; mRNA analysis of the cerebral cortex and hippocampus revealed expression change, indicating significant improvement in microglial activation, inflammation, excitotoxicity, and neurodegeneration at chronic measurement. These data suggest that, in the acute phase following injury, celecoxib protected against neuroinflammation, but exacerbated clinical cognitive disturbance. Moreover, while there was evidence of neuroprotective alleviation of mTBI pathophysiology at chronic measurement, there remained no change in clinical features.

Highlights

Mild traumatic brain injuries may result in persistent cognitive dysfunction [1]
Repetitive subconcussive impacts have been identified in driving the development of chronic clinical symptoms, which may progress to neurodegenerative diseases, such as chronic traumatic encephalopathy (CTE) [2]
COX-2 activity catalyzes the production of prostaglandin E2 (PGE2 ), which stimulates the release of glutamate from astrocytes, leading to excitotoxic effects [14], which may be a key driver of neuroinflammation that may result in dementia [15]

Summary

Introduction

Mild traumatic brain injuries (mTBI) may result in persistent cognitive dysfunction [1]. Inhibition of COX-2 promotes anti-inflammatory effects without these adverse effects by reducing (i) prostaglandins and thromboxanes, (ii) cytokines, and (iii) proteases This distinction has led to the focused development of selective COX-2 inhibitors, including celecoxib. Celecoxib demonstrates expected analgesic and anti-inflammatory effects, there are studies that provide evidence of neuroprotection from COX inhibition in conditions of neurotoxicity, neurodegeneration, and demyelination [8,9,10,11,12] These protective effects are not strictly resultant from reduced inflammation, as increased neuronal survival following COX-2 inhibition was not associated with decreased mRNA inflammatory signaling [13]. The process of increased excitotoxicity through COX-2 PGE2 and tumor necrosis factor (TNF) has been demonstrated in the pathophysiology of epilepsy [12]

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