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      Altered Hippocampal Neurogenesis during the First 7 Days after a Fluid Percussion Traumatic Brain Injury

      research-article
      1 ,
      Cell Transplantation
      SAGE Publications
      stem cells, hilar ectopic granule cells, doublecortin

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          Abstract

          Traumatic brain injury (TBI) is a devastating disorder causing negative outcomes in millions of people each year. Despite the alarming number of brain injuries and the long-term detrimental outcomes that can be associated with TBI, treatment options are lacking. Extensive investigation is underway, in hopes of identifying effective treatment strategies. Among the most state-of-the-art strategies is cell replacement therapy. TBI is a seemingly good candidate for cell replacement studies because there is often loss of neurons. However, translation of this therapy has not yet been successful. It is possible that a better understanding of endogenous neurogenic mechanisms after TBI could lead to more efficacious study designs using exogenous cell replacement strategies. Therefore, this study was designed to examine the number and migration of immature neurons at 1 and 7 d after a fluid percussion TBI. The results show that the number of immature neurons increases from 7 d after a fluid percussion injury (FPI), and there is ectopic migration of doublecortin (DCX+) immature neurons into the hilar region of the dentate gyrus. These results add important data to the current understanding of the endogenous neurogenic niche after TBI. Follow-up studies are needed to better understand the functional significance of elevated neurogenesis and aberrant migration into the hilus.

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          Pathophysiology Associated with Traumatic Brain Injury: Current Treatments and Potential Novel Therapeutics.

          Traumatic brain injury (TBI) is one of the leading causes of death of young people in the developed world. In the United States alone, 1.7 million traumatic events occur annually accounting for 50,000 deaths. The etiology of TBI includes traffic accidents, falls, gunshot wounds, sports, and combat-related events. TBI severity ranges from mild to severe. TBI can induce subtle changes in molecular signaling, alterations in cellular structure and function, and/or primary tissue injury, such as contusion, hemorrhage, and diffuse axonal injury. TBI results in blood-brain barrier (BBB) damage and leakage, which allows for increased extravasation of immune cells (i.e., increased neuroinflammation). BBB dysfunction and impaired homeostasis contribute to secondary injury that occurs from hours to days to months after the initial trauma. This delayed nature of the secondary injury suggests a potential therapeutic window. The focus of this article is on the (1) pathophysiology of TBI and (2) potential therapies that include biologics (stem cells, gene therapy, peptides), pharmacological (anti-inflammatory, antiepileptic, progrowth), and noninvasive (exercise, transcranial magnetic stimulation). In final, the review briefly discusses membrane/lipid rafts (MLR) and the MLR-associated protein caveolin (Cav). Interventions that increase Cav-1, MLR formation, and MLR recruitment of growth-promoting signaling components may augment the efficacy of pharmacologic agents or already existing endogenous neurotransmitters and neurotrophins that converge upon progrowth signaling cascades resulting in improved neuronal function after injury.
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            Embracing failure: What the Phase III progesterone studies can teach about TBI clinical trials

            Abstract Background: Despite positive preclinical studies and two positive Phase II clinical trials, two large Phase III clinical trials of progesterone treatment of acute traumatic brain injury (TBI) recently ended with negative results, so a 100% failure rate continues to plague the field of TBI trials. Methods: This paper reviews and analyses the trial structures and outcomes and discusses the implications of these failures for future drug and clinical trial development. Persistently negative trial outcomes have led to disinvestment in new drug research by companies and policy-makers and disappointment for patients and their families, failures which represent a major public health concern. The problem is not limited to TBI. Failure rates are high for trials in stroke, sepsis, cardiology, cancer and orthopaedics, among others. Results: This paper discusses some of the reasons why the Phase III trials have failed. These reasons may include faulty extrapolation from pre-clinical data in designing clinical trials and the use of subjective outcome measures that accurately reflect neither the nature of the deficits nor long-term quantitative recovery. Conclusions: Better definitions of injury and healing and better outcome measures are essential to change the embrace of failure that has dominated the field for over 30 years. This review offers suggestions to improve the situation.
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              Traumatic Brain Injury Severity Affects Neurogenesis in Adult Mouse Hippocampus.

              Traumatic brain injury (TBI) has been proven to enhance neural stem cell (NSC) proliferation in the hippocampal dentate gyrus. However, various groups have reported contradictory results on whether TBI increases neurogenesis, partially due to a wide range in the severities of injuries seen with different TBI models. To address whether the severity of TBI affects neurogenesis in the injured brain, we assessed neurogenesis in mouse brains receiving different severities of controlled cortical impact (CCI) with the same injury device. The mice were subjected to mild, moderate, or severe TBI by a CCI device. The effects of TBI severity on neurogenesis were evaluated at three stages: NSC proliferation, immature neurons, and newly-generated mature neurons. The results showed that mild TBI did not affect neurogenesis at any of the three stages. Moderate TBI promoted NSC proliferation without increasing neurogenesis. Severe TBI increased neurogenesis at all three stages. Our data suggest that the severity of injury affects adult neurogenesis in the hippocampus, and thus it may partially explain the inconsistent results of different groups regarding neurogenesis following TBI. Further understanding the mechanism of TBI-induced neurogenesis may provide a potential approach for using endogenous NSCs to protect against neuronal loss after trauma.
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                Author and article information

                Journal
                Cell Transplant
                Cell Transplant
                CLL
                spcll
                Cell Transplantation
                SAGE Publications (Sage CA: Los Angeles, CA )
                0963-6897
                1555-3892
                30 June 2017
                July 2017
                : 26
                : 7 , Special Issue: Traumatic Brain Injury
                : 1314-1318
                Affiliations
                [1 ]Department of Surgery, Texas A&M Health Science Center, Temple, TX, USA
                Author notes
                [*]Lee A. Shapiro, Department of Surgery, Texas A&M Health Science Center, 702 SW HK Dodgen Loop, Temple, TX 76504, USA. Email: lshapiro@ 123456medicine.tamhsc.edu
                Article
                10.1177_0963689717714099
                10.1177/0963689717714099
                5657729
                28933222
                db4db903-16c8-429a-82b7-0d311878c998
                © The Author(s) 2017

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 5 August 2016
                : 21 September 2016
                : 22 September 2016
                Categories
                Traumatic Brain Injury

                stem cells,hilar ectopic granule cells,doublecortin
                stem cells, hilar ectopic granule cells, doublecortin

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