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      Increased Seizure Susceptibility in Mice 30 Days after Fluid Percussion Injury

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          Traumatic brain injury (TBI) has been reported to increase seizure susceptibility and also contribute to the development of epilepsy. However, the mechanistic basis of the development of increased seizure susceptibility and epilepsy is not clear. Though there is substantial work done using rats, data are lacking regarding the use of mice in the fluid percussion injury (FPI) model. It is unclear if mice, like rats, will experience increased seizure susceptibility following FPI. The availability of a mouse model of increased seizure susceptibility after FPI would provide a basis for the use of genetically modified mice to study mechanism(s) of the development of post-traumatic epilepsy. Therefore, this study was designed to test the hypothesis that, mice subjected to a FPI develop increased seizure susceptibility to a subconvulsive dose of the chemoconvulsant, pentylenetetrazole (PTZ). Three groups of mice were used: FPI, sham, and naïve controls. On day 30 after FPI, mice from the three groups were injected with PTZ. The results showed that FPI mice exhibited an increased severity, frequency, and duration of seizures in response to PTZ injection compared with the sham and naïve control groups. Histopathological assessment was used to characterize the injury at 1, 3, 7, and 30 days after FPI. The results show that mice subjected to the FPI had a pronounced lesion and glial response that was centered at the FPI focus and peaked at 3 days. By 30 days, only minimal evidence of a lesion is observed, although there is evidence of a chronic glial response. These data are the first to demonstrate an early increase in seizure susceptibility following FPI in mice. Therefore, future studies can incorporate transgenic mice into this model to further elucidate mechanisms of TBI-induced increases in seizure susceptibility.

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          Most cited references 26

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          Microglia and neuroinflammation: a pathological perspective

          Microglia make up the innate immune system of the central nervous system and are key cellular mediators of neuroinflammatory processes. Their role in central nervous system diseases, including infections, is discussed in terms of a participation in both acute and chronic neuroinflammatory responses. Specific reference is made also to their involvement in Alzheimer's disease where microglial cell activation is thought to be critically important in the neurodegenerative process.
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            Prevalence of chronic pain after traumatic brain injury: a systematic review.

            The Centers for Disease Control and Prevention estimates that approximately 1.4 million US individuals sustain traumatic brain injuries (TBIs) per year. Previous reports suggest an association between TBI and chronic pain syndromes (eg, headache) thought to be more common in patients with mild TBI and in those who have sustained brain injury from violent rather than unintentional trauma. Comorbid psychiatric disorders such as posttraumatic stress disorder (PTSD) may also mediate chronic pain symptoms. To determine the prevalence of chronic pain as an underdiagnosed consequence of TBI and to review the interaction between chronic pain and severity of TBI as well as the characteristics of pain after TBI among civilians and combatants. The Ovid/MEDLINE database was searched for articles published between 1951 and February 2008 using any combination of the terms brain injury, pain, headache, blast injury, and combat (combat disorders, war, military medicine, wounds and injuries, military personnel, veterans). The PubMed and MD Consult databases were searched in a similar fashion. The Cochrane Collaboration, National Institutes of Health Clinical Trials Database, Meta-Register of Current Controlled Trials, and CRISP databases were searched using the keyword brain injury. All articles in peer-reviewed journals reporting original data on pain syndromes in adult patients with TBI with regard to pain prevalence, pain category, risk factors, pathogenesis, and clinical course were selected, and manual searches were performed of their reference lists. The data were pooled and prevalence rates calculated. Twenty-three studies (15 cross-sectional, 5 prospective, and 3 retrospective) including 4206 patients were identified. Twelve studies assessed headache pain in 1670 patients. Of these, 966 complained of chronic headache, yielding a prevalence of 57.8% (95% confidence interval [CI], 55.5%-60.2%). Among civilians, the prevalence of chronic pain was greater in patients with mild TBI (75.3% [95% CI, 72.7%-77.9%]) compared with moderate or severe TBI (32.1% [95% CI, 29.3%-34.9%]). Twenty studies including 3289 civilian patients with TBI yielded a chronic pain prevalence of 51.5% (95% CI, 49.8%-53.2%). Three studies assessed TBI among 917 veterans and yielded a pain prevalence of 43.1% (95% CI, 39.9%-46.3%). PTSD may mediate chronic pain, but brain injury appears to have an independent correlation with chronic pain. Chronic pain is a common complication of TBI. It is independent of psychologic disorders such as PTSD and depression and is common even among patients with apparently minor injuries to the brain.
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              Cytokines and brain excitability.

              Cytokines are molecules secreted by peripheral immune cells, microglia, astrocytes and neurons in the central nervous system. Peripheral or central inflammation is characterized by an upregulation of cytokines and their receptors in the brain. Emerging evidence indicates that pro-inflammatory cytokines modulate brain excitability. Findings from both the clinical literature and from in vivo and in vitro laboratory studies suggest that cytokines can increase seizure susceptibility and may be involved in epileptogenesis. Cellular mechanisms that underlie these effects include upregulation of excitatory glutamatergic transmission and downregulation of inhibitory GABAergic transmission. Copyright © 2012 Elsevier Inc. All rights reserved.

                Author and article information

                Front Neurol
                Front Neurol
                Front. Neurol.
                Frontiers in Neurology
                Frontiers Media S.A.
                21 March 2013
                : 4
                1Department of Surgery, Scott and White Hospital Temple, TX, USA
                2Central Texas Veterans Health Care System Temple, TX, USA
                3Department of Surgery, College of Medicine, Texas A&M Health Science Center Temple, TX, USA
                4Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center Temple, TX, USA
                Author notes

                Edited by: András Büki, University of Pécs, Hungary

                Reviewed by: Stefan Plantman, Karolinska Institutet, Sweden; Manuel B. Graeber, University of Sydney, Australia

                *Correspondence: Lee A. Shapiro, College of Medicine, Texas A&M Health Science Center, Building 205, 1901 South 1st Street, Temple, TX 76504, USA. e-mail: lshapiro@

                This article was submitted to Frontiers in Neurotrauma, a specialty of Frontiers in Neurology.

                Copyright © 2013 Mukherjee, Zeitouni, Cavarsan and Shapiro.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

                Page count
                Figures: 7, Tables: 2, Equations: 0, References: 30, Pages: 11, Words: 6157
                Original Research


                mouse models, pentylenetetrazole, post-traumatic epilepsy, traumatic brain injury


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