Abstract
BackgroundTrovafloxacin is a broad-spectrum antibiotic, recently identified as an inhibitor of pannexin-1 (Panx1) channels. Panx1 channels are important conduits for the adenosine triphosphate (ATP) release from live and dying cells that enhances the inflammatory response of immune cells. Elevated extracellular levels ATP released upon injury activate purinergic pathways in inflammatory cells that promote migration, proliferation, phagocytosis, and apoptotic signals. Here, we tested whether trovafloxacin administration attenuates the neuroinflammatory response and improves outcomes after brain trauma.MethodsThe murine controlled cortical impact (CCI) model was used to determine whether in vivo delivery of trovafloxacin has anti-inflammatory and neuroprotective actions after brain trauma. Locomotor deficit was assessed using the rotarod test. Levels of tissue damage markers and inflammation were measured using western blot, qPCR, and immunofluorescence. In vitro assays were used to evaluate whether trovafloxacin blocks ATP release and cell migration in a chemotactic-stimulated microglia cell line.ResultsTrovafloxacin treatment of CCI-injured mice significantly reduced tissue damage markers and improved locomotor deficits. In addition, trovafloxacin treatment significantly reduced mRNA levels of several pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), which correlates with an overall reduction in the accumulation of inflammatory cell types (neutrophils, microglia/macrophages, and astroglia) at the injury zone. To determine whether trovafloxacin exerted these effects by direct action on immune cells, we evaluated its effect on ATP release and cell migration using a chemotactic-stimulated microglial cell line. We found that trovafloxacin significantly inhibited both ATP release and migration of these cells.ConclusionOur results show that trovafloxacin administration has pronounced anti-inflammatory and neuroprotective effects following brain injury. These findings lay the foundation for future studies to directly test a role for Panx1 channels in pathological inflammation following brain trauma.
Highlights
Trovafloxacin is a broad-spectrum antibiotic, recently identified as an inhibitor of pannexin-1 (Panx1) channels
To determinate whether the improvements observed in the behavioral outcome of trovafloxacin-treated mice correlate with neuroprotective actions after cortical impact (CCI), we analyzed protein levels of matrix metallopeptidase 9 (MMP9) and neuronal α–ΙΙ spectrin breakdown products (SBDPs) in a b c
Among the multiple cell types that could be targeted by trovafloxacin in our model of traumatic brain injury (TBI), we focused on the accumulation of pro-inflammatory microglia and macrophages at the core of the injury site
Summary
Trovafloxacin is a broad-spectrum antibiotic, recently identified as an inhibitor of pannexin-1 (Panx1) channels. Panx channels are important conduits for the adenosine triphosphate (ATP) release from live and dying cells that enhances the inflammatory response of immune cells. Trovafloxacin was demonstrated to target human pannexin 1 (Panx1) channels at therapeutic concentrations reached in blood plasma [2]. Panx channels have emerged as important players in response to injury and inflammation [5,6,7]. ATP release via Panx channels enhances inflammatory responses in peripheral immune cells and is implicated in the activation of the inflammasome [4, 6, 8]. Panx channels expressed in endothelial cells can regulate the acute vascular inflammation by potentiating leukocyte emigration via ATP release [9]. It is likely that Panx channels contribute to neuroinflammatory responses upon brain injury, their potential as therapeutic targets in traumatic brain injury (TBI) remains elusive
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