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      Efficacy of N-Acetyl Cysteine in Traumatic Brain Injury

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          Abstract

          In this study, using two different injury models in two different species, we found that early post-injury treatment with N-Acetyl Cysteine (NAC) reversed the behavioral deficits associated with the TBI. These data suggest generalization of a protocol similar to our recent clinical trial with NAC in blast-induced mTBI in a battlefield setting [1], to mild concussion from blunt trauma. This study used both weight drop in mice and fluid percussion injury in rats. These were chosen to simulate either mild or moderate traumatic brain injury (TBI). For mice, we used novel object recognition and the Y maze. For rats, we used the Morris water maze. NAC was administered beginning 30–60 minutes after injury. Behavioral deficits due to injury in both species were significantly reversed by NAC treatment. We thus conclude NAC produces significant behavioral recovery after injury. Future preclinical studies are needed to define the mechanism of action, perhaps leading to more effective therapies in man.

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          Most cited references23

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          Place navigation impaired in rats with hippocampal lesions.

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            TRANSCRANIAL AMELIORATION OF INFLAMMATION AND CELL DEATH FOLLOWING BRAIN INJURY

            Traumatic brain injury (TBI) is increasingly appreciated to be highly prevalent and deleterious to neurological function 1, 2 . At present no effective treatment options are available, and little is known about the complex cellular response to TBI during its acute phase. To gain novel insights into TBI pathogenesis, we developed a novel closed-skull brain injury model that mirrors some pathological features associated with mild TBI in humans and used long-term intravital microscopy to study the dynamics of the injury response from its inception. Here we demonstrate that acute brain injury induces vascular damage, meningeal cell death, and the generation of reactive oxygen species (ROS) that ultimately breach the glial limitans and promote spread of the injury into the parenchyma. In response, the brain elicits a neuroprotective, purinergic receptor dependent inflammatory response characterized by meningeal neutrophil swarming and microglial reconstitution of the damaged glial limitans. We additionally show that the skull bone is permeable to small molecular weight compounds and use this delivery route to modulate inflammation and therapeutically ameliorate brain injury through transcranial administration of the ROS scavenger, glutathione. Our results provide novel insights into the acute cellular response to TBI and a means to locally deliver therapeutic compounds to the site of injury.
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              Extending the spontaneous preference test of recognition: evidence of object-location and object-context recognition.

              The natural preference for novel objects which is displayed by rats has been used as a behavioural index to test object recognition. In this series of experiments the standard spontaneous recognition task was extended to look at other types of recognition memory; memory for place (recognition that an object is in a location where previously there had been no object), memory for object in place (recognition that a specific object has changed position with another object) and memory for context (recognition that a familiar object is in a context different to that in which it was previously encountered). We also included a standard test of object recognition in which successful discrimination relied primarily on visual cues. In addition, we looked at how the differential exploration of objects varied within the 3 min of the test phase. The results showed that rats were sensitive to the changes made in all of the test conditions and that the level of discrimination varied within the 3 min test phase. In the standard condition and the context condition, the first 2 min were found to be the most sensitive period. In the two conditions involving a position change, discrimination was only evident in the first minute.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                16 April 2014
                : 9
                : 4
                : e90617
                Affiliations
                [1 ]Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
                [2 ]Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
                [3 ]Department of Otolaryngology, Neurobiology, Communication Sciences and Disorders, and Bioengineering, University of Pittsburgh, Pennsylvania, United States of America
                [4 ]Department of Otolaryngology, Spatial Orientation Center, Naval Medical Center San Diego, San Diego, California, United States of America
                [5 ]Graduate Program in Neuroregeneration, Taipei Medical University, Taipei City, Taiwan
                University of South Florida, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: JM BJH MEH CB. Performed the experiments: KE RB-G CP OZ ML JM. Analyzed the data: KE CP CB BJH. Wrote the paper: BJH JM CP MEH CB.

                Article
                PONE-D-14-01805
                10.1371/journal.pone.0090617
                3989181
                24740427
                7b0b2b96-b787-4f92-bb5c-9d2796d2a6f0
                Copyright @ 2014

                This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 13 January 2014
                : 1 February 2014
                Page count
                Pages: 7
                Funding
                This work was supported in part by the Lincoln Master Clinician in Neurosurgery Award to JM, [USPHS grant #NS070825]; and the National Science Council of Taiwan [#NSC98-2314-B-038-011-MY3], [NSC101-2321-B-038-005]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Neuroscience
                Cognitive Neuroscience
                Cognitive Neurology
                Medicine and Health Sciences
                Critical Care and Emergency Medicine
                Trauma Medicine
                Head Injury
                Neurorehabilitation and Trauma
                Neurology
                Neuropharmacology

                Uncategorized
                Uncategorized

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