Abstract
BackgroundTraumatic brain injury (TBI) induces secondary injury mechanisms, including dynamic interplay between ischemic, inflammatory and cytotoxic processes. We recently reported that administration of ATB-346 (2-(6-methoxynapthalen- 2-yl)-propionic acid 4-thiocarbamoyl-phenyl ester), a hydrogen sulfide-releasing cyclooxygenase inhibitor, showed marked beneficial effects in an animal model of spinal cord injury, significantly enhancing recovery of motor function and reducing the secondary inflammation and tissue injury.MethodsHere we evaluated the neuroprotective potential of ATB-346, a hydrogen sulfide-releasing derivative of naproxen, using the controlled cortical impact (CCI) injury model in mice, one of the most common models of TBI. Moreover, the aim of the present study was to carefully investigate molecular pathways and subtypes of glial cells involved in the protective effect of ATB-346 on inflammatory reaction associated with an experimental model of TBI. In these studies, TBI was induced in mice by CCI and mice were orally administered ATB-346, naproxen (both at 30 μmol/kg) or vehicle (dimethylsulfoxide:1% carboxymethylcellulose [5:95] suspension) one and six hours after brain trauma and once daily for 10 days.ResultsResults revealed that ATB-346 attenuated TBI-induced brain edema, suppressed TBI-induced neural cell death and improved neurological function. ATB-346 also significantly reduced the severity of inflammation and restored neurotrophic factors that characterized the secondary events of TBI.ConclusionsThese data demonstrate that ATB-346 can be efficacious in a TBI animal model by reducing the secondary inflammation and tissue injury. Therefore, ATB-346 could represent an interesting approach for the management of secondary damage following CNS diseases, counteracting behavioral changes and inflammatory process.
Highlights
Traumatic brain injury (TBI) induces secondary injury mechanisms, including dynamic interplay between ischemic, inflammatory and cytotoxic processes
Effect of ATB-346 on IκBα degradation and NFκBp65 translocation To investigate whether the cellular mechanism through ATB-346 could attenuate inflammatory processes we assessed Western blot analysis of the ipsilateral hemisphere after TBI, using an IκBα and an Nuclear factor κB (NFκB)-specific antibodies
Effect of ATB-346 on inducible nitric oxide synthase (iNOS) and COX-2 expression To determine the role of NO produced during TBI, iNOS expression was evaluated by Western blot analysis
Summary
Traumatic brain injury (TBI) induces secondary injury mechanisms, including dynamic interplay between ischemic, inflammatory and cytotoxic processes. Traumatic brain injury (TBI) is a growing public health concern worldwide. The pathophysiology of TBI can be divided into primary and secondary brain injury [2]. Primary injury results from the direct, physical brain trauma with tissue distortion, shearing, vascular injury and cell destruction probably related to rotational acceleration and deceleration inertial forces. Secondary brain injury is related to destructive inflammation and biochemical changes. Secondary injury onsets within minutes of primary injury, may last for several days and contributes to final outcome [3]. Primary and secondary brain injuries induce cerebral edema and bleeding. Secondary neuronal injury plays a key role in the severity of insult and subsequent clinical prognosis
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