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Dehbozorgi M, Maghsoudi MR, Mohammadi I, Firouzabadi SR, Mohammaditabar M, Oraee S, Aarabi A, Goodarzi M, Shafiee A, Bakhtiyari M. Incidence of anxiety after traumatic brain injury: a systematic review and meta-analysis. BMC Neurol 2024; 24:293. [PMID: 39174923 PMCID: PMC11340054 DOI: 10.1186/s12883-024-03791-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 08/01/2024] [Indexed: 08/24/2024] Open
Abstract
BACKGROUND Traumatic brain injury (TBI) is defined as acquired cerebral damage caused by an external mechanical impact, which has the potential to lead to transient or enduring debilitation. TBI is associated with many forms of long-lasting psychiatric conditions, including anxiety disorders. As anxiety is highly debilitating by causing impaired social functioning and decreased quality of life for the afflicted, especially in the form of anxiety disorders such as generalized anxiety disorder, certain efforts have been made to explore the factors associated with it, and one such factor is TBI. METHODS We searched PubMed, Scopus, and Web of Science on January 26th, 2024 for observational case-control or cohort or cross-sectional studies assessing the incidence of anxiety symptoms or disorders in patients with TBI compared to healthy individuals or the same individuals if pre-TBI information regarding anxiety was available. We calculated the pooled incidence and relative risk (RR) and 95% confidence interval (95CI) using the inverse variance method. Publication bias was assessed using Eggers's regression test. Quality assessment was performed using the Newcastle-Ottawa scale. Sub-group analyses were conducted for the type of anxiety (anxiety disorder vs anxiety symptoms), TBI severity, and type of anxiety disorders. RESULTS The incidence rate of anxiety after traumatic brain injury was 17.45% (95CI: 12.59%, 22.31%) in a total of 705,024 individuals. Moreover, TBI patients were found to be 1.9 times as likely to have anxiety compared to their non-TBI counterparts [Random effects model RR = 1.90 [1.62; 2.23], p-value < 0.0001] using a population of 569,875 TBI cases and 1,640,312 non-TBI controls. Sub-group analysis revealed TBI severity was not associated with anxiety and generalized anxiety disorder was the most common type of anxiety disorder reported post-TBI. CONCLUSION Patients who have experienced a TBI exhibit a significantly greater incidence of anxiety symptoms and anxiety disorders in the aftermath when compared to healthy individuals.
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Affiliation(s)
| | - Mohammad Reza Maghsoudi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
- Student Research Committee, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Ida Mohammadi
- Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Mahdi Mohammaditabar
- Student Research Committee, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Soroush Oraee
- Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Aryan Aarabi
- Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mana Goodarzi
- Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arman Shafiee
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.
- Student Research Committee, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.
- Alborz University of Medical Sciences, Karaj, Iran.
| | - Mahmood Bakhtiyari
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
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Liu SY, Kelly-Hedrick M, Temkin N, Barber J, Komisarow J, Hatfield J, Ohnuma T, Manley G, Treggiari MM, Colton K, Vavilala MS, Grandhi R, Laskowitz DT, Mathew JP, Hernandez A, James ML, Raghunathan K, Goldstein B, Krishnamoorthy V. Association of Early Dexmedetomidine Utilization With Clinical and Functional Outcomes Following Moderate-Severe Traumatic Brain Injury: A Transforming Clinical Research and Knowledge in Traumatic Brain Injury Study. Crit Care Med 2024; 52:607-617. [PMID: 37966330 PMCID: PMC10939970 DOI: 10.1097/ccm.0000000000006106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2023]
Abstract
OBJECTIVE To examine early sedation patterns, as well as the association of dexmedetomidine exposure, with clinical and functional outcomes among mechanically ventilated patients with moderate-severe traumatic brain injury (msTBI). DESIGN Retrospective cohort study with prospectively collected data. SETTING Eighteen Level-1 Trauma Centers, United States. PATIENTS Adult (age > 17) patients with msTBI (as defined by Glasgow Coma Scale < 13) who required mechanical ventilation from the Transforming Clinical Research and Knowledge in TBI (TRACK-TBI) study. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Using propensity-weighted models, we examined the association of early dexmedetomidine exposure (within the first 5 d of ICU admission) with the primary outcome of 6-month Glasgow Outcomes Scale Extended (GOS-E) and the following secondary outcomes: length of hospital stay, hospital mortality, 6-month Disability Rating Scale (DRS), and 6-month mortality. The study population included 352 subjects who required mechanical ventilation within 24 hours of admission. The initial sedative medication was propofol for 240 patients (68%), midazolam for 59 patients (17%), ketamine for 6 patients (2%), dexmedetomidine for 3 patients (1%), and 43 patients (12%) never received continuous sedation. Early dexmedetomidine was administered in 77 of the patients (22%), usually as a second-line agent. Compared with unexposed patients, early dexmedetomidine exposure was not associated with better 6-month GOS-E (weighted odds ratio [OR] = 1.48; 95% CI, 0.98-2.25). Early dexmedetomidine exposure was associated with lower DRS (weighted OR = -3.04; 95% CI, -5.88 to -0.21). In patients requiring ICP monitoring within the first 24 hours of admission, early dexmedetomidine exposure was associated with higher 6-month GOS-E score (OR 2.17; 95% CI, 1.24-3.80), lower DRS score (adjusted mean difference, -5.81; 95% CI, -9.38 to 2.25), and reduced length of hospital stay (hazard ratio = 1.50; 95% CI, 1.02-2.20). CONCLUSION Variation exists in early sedation choice among mechanically ventilated patients with msTBI. Early dexmedetomidine exposure was not associated with improved 6-month functional outcomes in the entire population, although may have clinical benefit in patients with indications for ICP monitoring.
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Affiliation(s)
- Sunny Yang Liu
- Critical Care and Perioperative Population Health Research (CAPER) Unit, Department of Anesthesiology, Duke University, Durham, NC
- Duke University School of Medicine, Durham, NC
| | - Margot Kelly-Hedrick
- Critical Care and Perioperative Population Health Research (CAPER) Unit, Department of Anesthesiology, Duke University, Durham, NC
- Duke University School of Medicine, Durham, NC
| | - Nancy Temkin
- Department of Biostatistics, University of Washington. Seattle, WA
- Department of Neurosurgery, University of Washington. Seattle, WA
| | - Jason Barber
- Department of Neurosurgery, University of Washington. Seattle, WA
| | | | - Jordan Hatfield
- Critical Care and Perioperative Population Health Research (CAPER) Unit, Department of Anesthesiology, Duke University, Durham, NC
- Duke University School of Medicine, Durham, NC
| | - Tetsu Ohnuma
- Critical Care and Perioperative Population Health Research (CAPER) Unit, Department of Anesthesiology, Duke University, Durham, NC
- Department of Anesthesiology, Duke University. Durham, NC
| | - Geoffrey Manley
- Brain and Spinal Injury Center, University of California, San Francisco, San Francisco, CA
| | - Miriam M. Treggiari
- Critical Care and Perioperative Population Health Research (CAPER) Unit, Department of Anesthesiology, Duke University, Durham, NC
- Department of Anesthesiology, Duke University. Durham, NC
| | | | - Monica S. Vavilala
- Department of Anesthesiology and Pain Medicine, University of Washington. Seattle, WA
| | - Ramesh Grandhi
- Department of Neurosurgery, University of Utah, Salt Lake City, UT
| | - Daniel T. Laskowitz
- Department of Neurosurgery, Duke University. Durham, NC
- Department of Anesthesiology, Duke University. Durham, NC
- Department Neurology, Duke University. Durham, NC
| | | | | | - Michael L. James
- Critical Care and Perioperative Population Health Research (CAPER) Unit, Department of Anesthesiology, Duke University, Durham, NC
- Department of Anesthesiology, Duke University. Durham, NC
- Department Neurology, Duke University. Durham, NC
| | - Karthik Raghunathan
- Critical Care and Perioperative Population Health Research (CAPER) Unit, Department of Anesthesiology, Duke University, Durham, NC
- Department of Anesthesiology, Duke University. Durham, NC
- Department of Population Health Sciences, Duke University. Durham, NC
| | - Ben Goldstein
- Departments of Biostatistics and Bioinformatics, Duke University. Durham, NC
| | - Vijay Krishnamoorthy
- Critical Care and Perioperative Population Health Research (CAPER) Unit, Department of Anesthesiology, Duke University, Durham, NC
- Department of Anesthesiology, Duke University. Durham, NC
- Department of Population Health Sciences, Duke University. Durham, NC
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3
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Chaikittisilpa N, Kiatchai T, Liu SY, Kelly-Hedrick M, Vavilala MS, Lele AV, Komisarow J, Ohnuma T, Colton K, Krishnamoorthy V. Incidence of Myocardial Injury and Cardiac Dysfunction After Adult Traumatic Brain Injury: A Systematic Review and Meta-analysis. J Neurosurg Anesthesiol 2023; 36:00008506-990000000-00085. [PMID: 39240312 PMCID: PMC11380044 DOI: 10.1097/ana.0000000000000945] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 10/16/2023] [Indexed: 09/07/2024]
Abstract
Myocardial injury and cardiac dysfunction after traumatic brain injury (TBI) have been reported in observational studies, but there is no robust estimate of their incidences. We conducted a systematic review and meta-analysis to estimate the pooled incidence of myocardial injury and cardiac dysfunction among adult patients with TBI. A literature search was conducted using MEDLINE and EMBASE databases from inception to November 2022. Observational studies were included if they reported at least one abnormal electrocardiographic finding, elevated cardiac troponin level, or echocardiographic evaluation of systolic function or left ventricular wall motion in adult patients with TBI. Myocardial injury was defined as elevated cardiac troponin level according to the original studies and cardiac dysfunction was defined as the presence of left ventricular ejection fraction <50% or regional wall motion abnormalities assessed by echocardiography. The meta-analysis of the pooled incidence of myocardial injury and cardiac dysfunction was performed using random-effect models. The pooled estimated incidence of myocardial injury after TBI (17 studies, 3,773 participants) was 33% (95% CI: 27%-39%, I2:s 93%), and the pooled estimated incidence of cardiac dysfunction after TBI (9 studies, 557 participants) was 16.% (95% CI: 9%-25.%, I2: 84%). Although there was significant heterogeneity between studies and potential overestimation of the incidence of myocardial injury and cardiac dysfunction, our findings suggest that myocardial injury occurs in approximately one-third of adults after TBI, and cardiac dysfunction occurs in approximately one-sixth of patients with TBI.
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Affiliation(s)
- Nophanan Chaikittisilpa
- Department of Anesthesiology, Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Harborview Injury Prevention and Research Center, University of Washington, Seattle, WA, USA
| | - Taniga Kiatchai
- Department of Anesthesiology, Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Harborview Injury Prevention and Research Center, University of Washington, Seattle, WA, USA
| | - Sunny Yang Liu
- Department of Anesthesiology, Critical Care and Perioperative Population Health Research (CAPER) Unit, Duke University, Durham, NC, USA
- Duke University School of Medicine, Durham, NC, USA
| | - Margot Kelly-Hedrick
- Department of Anesthesiology, Critical Care and Perioperative Population Health Research (CAPER) Unit, Duke University, Durham, NC, USA
- Duke University School of Medicine, Durham, NC, USA
| | - Monica S Vavilala
- Harborview Injury Prevention and Research Center, University of Washington, Seattle, WA, USA
- Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA
| | - Abhijit V Lele
- Harborview Injury Prevention and Research Center, University of Washington, Seattle, WA, USA
- Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA
| | - Jordan Komisarow
- Department of Anesthesiology, Critical Care and Perioperative Population Health Research (CAPER) Unit, Duke University, Durham, NC, USA
- Department of Neurosurgery
| | - Tetsu Ohnuma
- Department of Anesthesiology, Critical Care and Perioperative Population Health Research (CAPER) Unit, Duke University, Durham, NC, USA
- Department of Anesthesiology
| | | | - Vijay Krishnamoorthy
- Harborview Injury Prevention and Research Center, University of Washington, Seattle, WA, USA
- Department of Anesthesiology, Critical Care and Perioperative Population Health Research (CAPER) Unit, Duke University, Durham, NC, USA
- Department of Anesthesiology
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Chu E, Mychasiuk R, Green TRF, Zamani A, Dill LK, Sharma R, Raftery AL, Tsantikos E, Hibbs ML, Semple BD. Regulation of microglial responses after pediatric traumatic brain injury: exploring the role of SHIP-1. Front Neurosci 2023; 17:1276495. [PMID: 37901420 PMCID: PMC10603304 DOI: 10.3389/fnins.2023.1276495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Accepted: 09/18/2023] [Indexed: 10/31/2023] Open
Abstract
Introduction Severe traumatic brain injury (TBI) is the world's leading cause of permanent neurological disability in children. TBI-induced neurological deficits may be driven by neuroinflammation post-injury. Abnormal activity of SH2 domain-containing inositol 5' phosphatase-1 (SHIP-1) has been associated with dysregulated immunological responses, but the role of SHIP-1 in the brain remains unclear. The current study investigated the immunoregulatory role of SHIP-1 in a mouse model of moderate-severe pediatric TBI. Methods SHIP-1+/- and SHIP-1-/- mice underwent experimental TBI or sham surgery at post-natal day 21. Brain gene expression was examined across a time course, and immunofluorescence staining was evaluated to determine cellular immune responses, alongside peripheral serum cytokine levels by immunoassays. Brain tissue volume loss was measured using volumetric analysis, and behavior changes both acutely and chronically post-injury. Results Acutely, inflammatory gene expression was elevated in the injured cortex alongside increased IBA-1 expression and altered microglial morphology; but to a similar extent in SHIP-1-/- mice and littermate SHIP-1+/- control mice. Similarly, the infiltration and activation of CD68-positive macrophages, and reactivity of GFAP-positive astrocytes, was increased after TBI but comparable between genotypes. TBI increased anxiety-like behavior acutely, whereas SHIP-1 deficiency alone reduced general locomotor activity. Chronically, at 12-weeks post-TBI, SHIP-1-/- mice exhibited reduced body weight and increased circulating cytokines. Pro-inflammatory gene expression in the injured hippocampus was also elevated in SHIP-1-/- mice; however, GFAP immunoreactivity at the injury site in TBI mice was lower. TBI induced a comparable loss of cortical and hippocampal tissue in both genotypes, while SHIP-1-/- mice showed reduced general activity and impaired working memory, independent of TBI. Conclusion Together, evidence does not support SHIP-1 as an essential regulator of brain microglial morphology, brain immune responses, or the extent of tissue damage after moderate-severe pediatric TBI in mice. However, our data suggest that reduced SHIP-1 activity induces a greater inflammatory response in the hippocampus chronically post-TBI, warranting further investigation.
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Affiliation(s)
- Erskine Chu
- Department of Neuroscience, Monash University, Melbourne, VIC, Australia
- Department of Immunology, Monash University, Melbourne, VIC, Australia
| | - Richelle Mychasiuk
- Department of Neuroscience, Monash University, Melbourne, VIC, Australia
- Deparment of Neurology, Alfred Health, Prahran, VIC, Australia
| | - Tabitha R. F. Green
- Department of Integrative Physiology, The University of Colorado Boulder, Boulder, CO, United States
| | - Akram Zamani
- Department of Neuroscience, Monash University, Melbourne, VIC, Australia
| | - Larissa K. Dill
- Department of Neuroscience, Monash University, Melbourne, VIC, Australia
- Alfred Health, Prahran, VIC, Australia
| | - Rishabh Sharma
- Department of Neuroscience, Monash University, Melbourne, VIC, Australia
| | - April L. Raftery
- Department of Immunology, Monash University, Melbourne, VIC, Australia
| | - Evelyn Tsantikos
- Department of Immunology, Monash University, Melbourne, VIC, Australia
| | - Margaret L. Hibbs
- Department of Immunology, Monash University, Melbourne, VIC, Australia
| | - Bridgette D. Semple
- Department of Neuroscience, Monash University, Melbourne, VIC, Australia
- Deparment of Neurology, Alfred Health, Prahran, VIC, Australia
- Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Parkville, VIC, Australia
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5
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Weil ZM, White B, Whitehead B, Karelina K. The role of the stress system in recovery after traumatic brain injury: A tribute to Bruce S. McEwen. Neurobiol Stress 2022; 19:100467. [PMID: 35720260 PMCID: PMC9201063 DOI: 10.1016/j.ynstr.2022.100467] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 05/25/2022] [Accepted: 06/02/2022] [Indexed: 11/21/2022] Open
Abstract
Traumatic brain injury (TBI) represents a major public health concern. Although the majority of individuals that suffer mild-moderate TBI recover relatively quickly, a substantial subset of individuals experiences prolonged and debilitating symptoms. An exacerbated response to physiological and psychological stressors after TBI may mediate poor functional recovery. Individuals with TBI can suffer from poor stress tolerance, impairments in the ability to evaluate stressors, and poor initiation (and cessation) of neuroendocrine stress responses, all of which can exacerbate TBI-mediated dysfunction. Here, we pay tribute to the pioneering neuroendocrinologist Dr. Bruce McEwen by discussing the ways in which his work on stress physiology and allostatic loading impacts the TBI patient population both before and after their injuries. Specifically, we will discuss the modulatory role of hypothalamic-pituitary-adrenal axis responses immediately after TBI and later in recovery. We will also consider the impact of stressors and stress responses in promoting post-concussive syndrome and post-traumatic stress disorders, two common sequelae of TBI. Finally, we will explore the role of early life stressors, prior to brain injuries, as modulators of injury outcomes.
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Affiliation(s)
- Zachary M. Weil
- Department of Neuroscience and Rockefeller Neuroscience Institute, West Virginia University, 108 Biomedical Rd, Morgantown, WV, 26506, USA
| | - Brishti White
- Department of Neuroscience and Rockefeller Neuroscience Institute, West Virginia University, 108 Biomedical Rd, Morgantown, WV, 26506, USA
| | - Bailey Whitehead
- Department of Neuroscience and Rockefeller Neuroscience Institute, West Virginia University, 108 Biomedical Rd, Morgantown, WV, 26506, USA
| | - Kate Karelina
- Department of Neuroscience and Rockefeller Neuroscience Institute, West Virginia University, 108 Biomedical Rd, Morgantown, WV, 26506, USA
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6
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Ferrara M, Bertozzi G, Zanza C, Longhitano Y, Piccolella F, Lauritano CE, Volonnino G, Manetti AC, Maiese A, La Russa R. Traumatic Brain Injury and Gut Brain Axis: The Disruption of an Alliance. Rev Recent Clin Trials 2022; 17:268-279. [PMID: 35733301 DOI: 10.2174/1574887117666220622143423] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 03/13/2022] [Accepted: 12/15/2022] [Indexed: 01/15/2023]
Abstract
BACKGROUND Traumatic brain injury (TBI) can be considered a "silent epidemic", causing morbidity, disability, and mortality in all age cohorts. Therefore, a greater understanding of the underlying pathophysiological intricate mechanisms and interactions with other organs and systems is necessary to intervene not only in the treatment but also in the prevention of complications. In this complex of reciprocal interactions, the complex brain-gut axis has captured a growing interest. SCOPE The purpose of this manuscript is to examine and systematize existing evidence regarding the pathophysiological processes that occur following TBI and the influences exerted on these by the brain-gut axis. LITERATURE REVIEW A systematic review of the literature was conducted according to the PRISMA methodology. On the 8th of October 2021, two independent databases were searched: PubMed and Scopus. Following the inclusion and exclusion criteria selected, 24 (12 from PubMed and 12 from Scopus) eligible manuscripts were included in the present review. Moreover, references from the selected articles were also updated following the criteria mentioned above, yielding 91 included manuscripts. DISCUSSION Published evidence suggests that the brain and gut are mutually influenced through four main pathways: microbiota, inflammatory, nervous, and endocrine. CONCLUSION These pathways are bidirectional and interact with each other. However, the studies conducted so far mainly involve animals. An autopsy methodological approach to corpses affected by traumatic brain injury or intestinal pathology could represent the keystone for future studies to clarify the complex pathophysiological processes underlying the interaction between these two main systems.
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Affiliation(s)
- Michela Ferrara
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Viale Regina Elena 336, Rome, 00161, Italy
| | - Giuseppe Bertozzi
- Section of Legal Medicine, Department of Clinical and Experimental Medicine, University of Foggia, Italy
| | - Christian Zanza
- Foundation of "Ospedale Alba-Bra Onlus and Department of Anesthesia and Critical Care and Emergency Medicine- "Michele and Pietro Ferrero Hospital" Verduno, Cuneo, Italy
| | - Yaroslava Longhitano
- Department of Anesthesia and Critical Care - AON SS Antonio and Biagio and Cesare Arrigo Hospital- Alessandria, Italy
| | - Fabio Piccolella
- Department of Anesthesia and Critical Care - AON SS Antonio and Biagio and Cesare Arrigo Hospital- Alessandria, Italy
| | - Cristiano Ernesto Lauritano
- Department of Anesthesia and Critical Care - AON SS Antonio and Biagio and Cesare Arrigo Hospital- Alessandria, Italy
| | - Gianpietro Volonnino
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Viale Regina Elena 336, Rome, 00161, Italy
| | - Alice Chiara Manetti
- Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, Pisa, 56126, Italy
| | - Aniello Maiese
- Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, Pisa, 56126, Italy
| | - Raffaele La Russa
- Section of Legal Medicine, Department of Clinical and Experimental Medicine, University of Foggia, Italy
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7
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Komoltsev IG, Tret'yakova LV, Frankevich SO, Shirobokova NI, Volkova AA, Butuzov AV, Novikova MR, Kvichansky AA, Moiseeva YV, Onufriev MV, Bolshakov AP, Gulyaeva NV. Neuroinflammatory Cytokine Response, Neuronal Death, and Microglial Proliferation in the Hippocampus of Rats During the Early Period After Lateral Fluid Percussion-Induced Traumatic Injury of the Neocortex. Mol Neurobiol 2021; 59:1151-1167. [PMID: 34855115 DOI: 10.1007/s12035-021-02668-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 11/25/2021] [Indexed: 02/01/2023]
Abstract
Time course of changes in neuroinflammatory processes in the dorsal and ventral hippocampus was studied during the early period after lateral fluid percussion-induced neocortical traumatic brain injury (TBI) in the ipsilateral and contralateral hemispheres. In the ipsilateral hippocampus, neuroinflammation (increase in expression of pro-inflammatory cytokines) was evident from day 1 after TBI and ceased by day 14, while in the contralateral hippocampus, it was mainly limited to the dorsal part on day 1. TBI induced an increase in hippocampal corticosterone level on day 3 bilaterally and an accumulation of Il1b on day 1 in the ipsilateral hippocampus. Activation of microglia was observed from day 7 in different hippocampal areas of both hemispheres. Neuronal cell loss was detected in the ipsilateral dentate gyrus on day 3 and extended to the contralateral hippocampus by day 7 after TBI. The data suggest that TBI results in distant hippocampal damage (delayed neurodegeneration in the dentate gyrus and microglia proliferation in both the ipsilateral and contralateral hippocampus), the time course of this damage being different from that of the neuroinflammatory response.
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Affiliation(s)
- Ilia G Komoltsev
- Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117485, Moscow, Russia.,Research and Clinical Center for Neuropsychiatry of Moscow Healthcare Department, 115419, Moscow, Russia
| | - Liya V Tret'yakova
- Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117485, Moscow, Russia
| | - Stepan O Frankevich
- Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117485, Moscow, Russia.,Research and Clinical Center for Neuropsychiatry of Moscow Healthcare Department, 115419, Moscow, Russia
| | - Natalia I Shirobokova
- Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117485, Moscow, Russia
| | - Aleksandra A Volkova
- Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117485, Moscow, Russia
| | - Alexey V Butuzov
- Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117485, Moscow, Russia
| | - Margarita R Novikova
- Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117485, Moscow, Russia
| | - Alexey A Kvichansky
- Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117485, Moscow, Russia
| | - Yulia V Moiseeva
- Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117485, Moscow, Russia
| | - Mikhail V Onufriev
- Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117485, Moscow, Russia.,Research and Clinical Center for Neuropsychiatry of Moscow Healthcare Department, 115419, Moscow, Russia
| | - Alexey P Bolshakov
- Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117485, Moscow, Russia
| | - Natalia V Gulyaeva
- Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117485, Moscow, Russia. .,Research and Clinical Center for Neuropsychiatry of Moscow Healthcare Department, 115419, Moscow, Russia.
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8
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Parker KN, Donovan MH, Smith K, Noble-Haeusslein LJ. Traumatic Injury to the Developing Brain: Emerging Relationship to Early Life Stress. Front Neurol 2021; 12:708800. [PMID: 34484104 PMCID: PMC8416304 DOI: 10.3389/fneur.2021.708800] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 07/22/2021] [Indexed: 12/01/2022] Open
Abstract
Despite the high incidence of brain injuries in children, we have yet to fully understand the unique vulnerability of a young brain to an injury and key determinants of long-term recovery. Here we consider how early life stress may influence recovery after an early age brain injury. Studies of early life stress alone reveal persistent structural and functional impairments at adulthood. We consider the interacting pathologies imposed by early life stress and subsequent brain injuries during early brain development as well as at adulthood. This review outlines how early life stress primes the immune cells of the brain and periphery to elicit a heightened response to injury. While the focus of this review is on early age traumatic brain injuries, there is also a consideration of preclinical models of neonatal hypoxia and stroke, as each further speaks to the vulnerability of the brain and reinforces those characteristics that are common across each of these injuries. Lastly, we identify a common mechanistic trend; namely, early life stress worsens outcomes independent of its temporal proximity to a brain injury.
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Affiliation(s)
- Kaila N. Parker
- Department of Neurology, Dell Medical School, University of Texas at Austin, Austin, TX, United States
- Department of Psychology, Behavioral Neuroscience, College of Liberal Arts, University of Texas at Austin, Austin, TX, United States
| | - Michael H. Donovan
- Department of Neurology, Dell Medical School, University of Texas at Austin, Austin, TX, United States
- Department of Psychology, Behavioral Neuroscience, College of Liberal Arts, University of Texas at Austin, Austin, TX, United States
| | - Kylee Smith
- Department of Neurology, Dell Medical School, University of Texas at Austin, Austin, TX, United States
- Department of Psychology, Behavioral Neuroscience, College of Liberal Arts, University of Texas at Austin, Austin, TX, United States
| | - Linda J. Noble-Haeusslein
- Department of Neurology, Dell Medical School, University of Texas at Austin, Austin, TX, United States
- Department of Psychology, Behavioral Neuroscience, College of Liberal Arts, University of Texas at Austin, Austin, TX, United States
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9
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Daneva E, Makris K, Korompeli A, Muurlink O, Kaklamanos I, Fildissis G, Vlachos K, Myrianthefs P. Saliva cortisol levels and physiological parameter fluctuations in mild traumatic brain injury patients compared to controls. Int J Neurosci 2021; 133:612-620. [PMID: 34228947 DOI: 10.1080/00207454.2021.1951264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
BACKGROUND Evidence suggests that fluctuations of cortisol and physiological parameters can emerge during the course of mild Traumatic Brain Injury (mTBI). OBJECTIVE To investigate fluctuations of cortisol and physiological parametersduring the acute phase of mTBI in hospitalized patients. METHODS 30 participants (19 patients with mTBI and 11 controls) were examined for saliva cortisol dynamics, heart rate (HR), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), mean arterial pressure (MAP) and body temperature (BT) fluctuations for four consecutive days. Also, the participants completed the Athens Insomnia Scale and Epworth Sleepiness Scales, in order to check for sleep problems. RESULTS Patients showed elevated levels of cortisol relative to controls (peak at 8 am and lowest levels at 12 am), as well as for most physiological parameters. MAP was significantly higher for patients throughout the measurement period, and BT was elevated for patients relative to controls at almost all measurements of the first and second day. Mean HR tended to track at non-significantly higher levels for the mTBI group. Patients' sleepiness and insomnia values (ESS and AIS) were initially significantly higher relative to controls but the difference dissipated by day 4. CONCLUSION The increase in absolute values of cortisol and physiological parameters measurements, indicates that in the acute phase of mTBI, a stressful process is activated which may affect sleep quality as well.Supplemental data for this article is available online at at doi: 10.1080/00207454.2021.1951264.
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Affiliation(s)
| | - Konstantinos Makris
- Clinical Biochemistry Department, KAT General Hospital, Kifissia, Athens, Greece
| | - Anna Korompeli
- National and Kapodistrian University of Athens, School of Health Sciences, Department of Nursing, "AgioiAnargyroi" General Hospital, Athens, Greece, Noufaron & Timiou Stavrou, Kaliftaki, Nea Kifissia, Athens, Greece
| | - Olav Muurlink
- Central Queensland University, Brisbane, Griffith Institute of Educational Research, Brisbane, Australia
| | - Ioannis Kaklamanos
- National and Kapodistrian University of Athens, School of Health Sciences, Department of Nursing, "AgioiAnargyroi" General Hospital, Athens, Greece, Noufaron & Timiou Stavrou, Kaliftaki, Nea Kifissia, Athens, Greece
| | - George Fildissis
- National and Kapodistrian University of Athens, School of Health Sciences, Department of Nursing, "AgioiAnargyroi" General Hospital, Athens, Greece, Noufaron & Timiou Stavrou, Kaliftaki, Nea Kifissia, Athens, Greece
| | | | - Pavlos Myrianthefs
- National and Kapodistrian University of Athens, School of Health Sciences, Department of Nursing, "AgioiAnargyroi" General Hospital, Athens, Greece, Noufaron & Timiou Stavrou, Kaliftaki, Nea Kifissia, Athens, Greece
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10
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Sabet N, Soltani Z, Khaksari M. Multipotential and systemic effects of traumatic brain injury. J Neuroimmunol 2021; 357:577619. [PMID: 34058510 DOI: 10.1016/j.jneuroim.2021.577619] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 05/07/2021] [Accepted: 05/24/2021] [Indexed: 02/06/2023]
Abstract
Traumatic brain injury (TBI) is one of the leading causes of disability and mortality of people at all ages. Biochemical, cellular and physiological events that occur during primary injury lead to a delayed and long-term secondary damage that can last from hours to years. Secondary brain injury causes tissue damage in the central nervous system and a subsequent strong and rapid inflammatory response that may lead to persistent inflammation. However, this inflammatory response is not limited to the brain. Inflammatory mediators are transferred from damaged brain tissue to the bloodstream and produce a systemic inflammatory response in peripheral organs, including the cardiovascular, pulmonary, gastrointestinal, renal and endocrine systems. Complications of TBI are associated with its multiple and systemic effects that should be considered in the treatment of TBI patients. Therefore, in this review, an attempt was made to examine the systemic effects of TBI in detail. It is hoped that this review will identify the mechanisms of injury and complications of TBI, and open a window for promising treatment in TBI complications.
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Affiliation(s)
- Nazanin Sabet
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran; Department of Physiology and Pharmacology, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Zahra Soltani
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran; Department of Physiology and Pharmacology, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
| | - Mohammad Khaksari
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
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11
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Bromberg CE, Condon AM, Ridgway SW, Krishna G, Garcia-Filion PC, Adelson PD, Rowe RK, Thomas TC. Sex-Dependent Pathology in the HPA Axis at a Sub-acute Period After Experimental Traumatic Brain Injury. Front Neurol 2020; 11:946. [PMID: 33101162 PMCID: PMC7554641 DOI: 10.3389/fneur.2020.00946] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Accepted: 07/21/2020] [Indexed: 12/18/2022] Open
Abstract
Over 2.8 million traumatic brain injuries (TBIs) are reported in the United States annually, of which, over 75% are mild TBIs with diffuse axonal injury (DAI) as the primary pathology. TBI instigates a stress response that stimulates the hypothalamic-pituitary-adrenal (HPA) axis concurrently with DAI in brain regions responsible for feedback regulation. While the incidence of affective symptoms is high in both men and women, presentation is more prevalent and severe in women. Few studies have longitudinally evaluated the etiology underlying late-onset affective symptoms after mild TBI and even fewer have included females in the experimental design. In the experimental TBI model employed in this study, evidence of chronic HPA dysregulation has been reported at 2 months post-injury in male rats, with peak neuropathology in other regions of the brain at 7 days post-injury (DPI). We predicted that mechanisms leading to dysregulation of the HPA axis in male and female rats would be most evident at 7 DPI, the sub-acute time point. Young adult age-matched male and naturally cycling female Sprague Dawley rats were subjected to midline fluid percussion injury (mFPI) or sham surgery. Corticotropin releasing hormone, gliosis, and glucocorticoid receptor (GR) levels were evaluated in the hypothalamus and hippocampus, along with baseline plasma adrenocorticotropic hormone (ACTH) and adrenal gland weights. Microglial response in the paraventricular nucleus of the hypothalamus indicated mild neuroinflammation in males compared to sex-matched shams, but not females. Evidence of microglia activation in the dentate gyrus of the hippocampus was robust in both sexes compared with uninjured shams and there was evidence of a significant interaction between sex and injury regarding microglial cell count. GFAP intensity and astrocyte numbers increased as a function of injury, indicative of astrocytosis. GR protein levels were elevated 30% in the hippocampus of females in comparison to sex-matched shams. These data indicate sex-differences in sub-acute pathophysiology following DAI that precede late-onset HPA axis dysregulation. Further understanding of the etiology leading up to late-onset HPA axis dysregulation following DAI could identify targets to stabilize feedback, attenuate symptoms, and improve efficacy of rehabilitation and overall recovery.
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Affiliation(s)
- Caitlin E Bromberg
- Barrow Neurological Institute at Phoenix Children's Hospital, Phoenix, AZ, United States.,Department of Child Health, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, United States
| | - Andrew M Condon
- Department of Child Health, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, United States.,Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom
| | - Samantha W Ridgway
- Department of Child Health, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, United States.,Department of Biology, School of Life Sciences, Arizona State University, Tempe, AZ, United States
| | - Gokul Krishna
- Barrow Neurological Institute at Phoenix Children's Hospital, Phoenix, AZ, United States.,Department of Child Health, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, United States
| | - Pamela C Garcia-Filion
- Department of Biomedical Informatics, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, United States
| | - P David Adelson
- Barrow Neurological Institute at Phoenix Children's Hospital, Phoenix, AZ, United States.,Department of Child Health, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, United States.,Department of Neurosurgery, Mayo Clinic School of Medicine, Phoenix, AZ, United States.,School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, United States
| | - Rachel K Rowe
- Barrow Neurological Institute at Phoenix Children's Hospital, Phoenix, AZ, United States.,Department of Child Health, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, United States.,Phoenix VA Health Care System, Phoenix, AZ, United States
| | - Theresa Currier Thomas
- Barrow Neurological Institute at Phoenix Children's Hospital, Phoenix, AZ, United States.,Department of Child Health, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, United States.,Phoenix VA Health Care System, Phoenix, AZ, United States
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12
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McCabe JT, Tucker LB. Sex as a Biological Variable in Preclinical Modeling of Blast-Related Traumatic Brain Injury. Front Neurol 2020; 11:541050. [PMID: 33101170 PMCID: PMC7554632 DOI: 10.3389/fneur.2020.541050] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Accepted: 08/14/2020] [Indexed: 12/14/2022] Open
Abstract
Approaches to furthering our understanding of the bioeffects, behavioral changes, and treatment options following exposure to blast are a worldwide priority. Of particular need is a more concerted effort to employ animal models to determine possible sex differences, which have been reported in the clinical literature. In this review, clinical and preclinical reports concerning blast injury effects are summarized in relation to sex as a biological variable (SABV). The review outlines approaches that explore the pertinent role of sex chromosomes and gonadal steroids for delineating sex as a biological independent variable. Next, underlying biological factors that need exploration for blast effects in light of SABV are outlined, including pituitary, autonomic, vascular, and inflammation factors that all have evidence as having important SABV relevance. A major second consideration for the study of SABV and preclinical blast effects is the notable lack of consistent model design—a wide range of devices have been employed with questionable relevance to real-life scenarios—as well as poor standardization for reporting of blast parameters. Hence, the review also provides current views regarding optimal design of shock tubes for approaching the problem of primary blast effects and sex differences and outlines a plan for the regularization of reporting. Standardization and clear description of blast parameters will provide greater comparability across models, as well as unify consensus for important sex difference bioeffects.
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Affiliation(s)
- Joseph T McCabe
- Pre-clinical Studies Core, Center for Neuroscience and Regenerative Medicine, Bethesda, IL, United States.,Department of Anatomy, Physiology & Genetics, F.E. Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
| | - Laura B Tucker
- Pre-clinical Studies Core, Center for Neuroscience and Regenerative Medicine, Bethesda, IL, United States.,Department of Anatomy, Physiology & Genetics, F.E. Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
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13
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Bhatt D, Hazari A, Yamakawa GR, Salberg S, Sgro M, Shultz SR, Mychasiuk R. Investigating the cumulative effects of Δ9-tetrahydrocannabinol and repetitive mild traumatic brain injury on adolescent rats. Brain Commun 2020; 2:fcaa042. [PMID: 32954298 PMCID: PMC7425386 DOI: 10.1093/braincomms/fcaa042] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 03/04/2020] [Accepted: 03/12/2020] [Indexed: 12/24/2022] Open
Abstract
The prevalence of mild traumatic brain injury is highest amongst the adolescent population and can lead to complications including neuroinflammation and excitotoxicity. Also pervasive in adolescents is recreational cannabis use. Δ9-Tetrahydrocannabinol, the main psychoactive component of cannabis, is known to have anti-inflammatory properties and serves as a neuroprotective agent against excitotoxicity. Thus, we investigated the effects of Δ9-tetrahydrocannabinol on recovery when administered either prior to or following repeated mild brain injuries. Male and female Sprague-Dawley rats were randomly assigned to receive Δ9-tetrahydrocannabinol or vehicle either prior to or following the repeated injuries. Rats were then tested on a behavioural test battery designed to measure post-concussive symptomology. The hippocampus, nucleus accumbens and prefrontal cortex were extracted from all animals to examine mRNA expression changes (Bdnf, Cnr1, Comt, GR, Iba-1 and Vegf-2R). We hypothesized that, in both experiments, Δ9-tetrahydrocannabinol administration would provide neuroprotection against mild injury outcomes and confer therapeutic benefit. Δ9-Tetrahydrocannabinol administration following repeated mild traumatic brain injury was beneficial to three of the six behavioural outcomes affected by injury (reducing anxiety and depressive-like behaviours while also mitigating injury-induced deficits in short-term working memory). Δ9-Tetrahydrocannabinol administration following injury also showed beneficial effects on the expression of Cnr1, Comt and Vegf-2R in the hippocampus, nucleus accumbens and prefrontal cortex. There were no notable benefits of Δ9-tetrahydrocannabinol when administered prior to injury, suggesting that Δ9-tetrahydrocannabinol may have potential therapeutic benefit on post-concussive symptomology when administered post-injury, but not pre-injury.
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Affiliation(s)
- Dhyey Bhatt
- Department of Psychology, Alberta Children’s Hospital Research Institute, Hotchkiss Brain Institute, The University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Ali Hazari
- Department of Psychology, Alberta Children’s Hospital Research Institute, Hotchkiss Brain Institute, The University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Glenn R Yamakawa
- Department of Psychology, Alberta Children’s Hospital Research Institute, Hotchkiss Brain Institute, The University of Calgary, Calgary, AB T2N 4N1, Canada
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
| | - Sabrina Salberg
- Department of Psychology, Alberta Children’s Hospital Research Institute, Hotchkiss Brain Institute, The University of Calgary, Calgary, AB T2N 4N1, Canada
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
| | - Marissa Sgro
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
| | - Sandy R Shultz
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
- Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC 3050, Australia
| | - Richelle Mychasiuk
- Department of Psychology, Alberta Children’s Hospital Research Institute, Hotchkiss Brain Institute, The University of Calgary, Calgary, AB T2N 4N1, Canada
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
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14
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Anwer M, Lara-Valderrabano L, Karttunen J, Ndode-Ekane XE, Puhakka N, Pitkänen A. Acute Downregulation of Novel Hypothalamic Protein Sushi Repeat-Containing Protein X-Linked 2 after Experimental Traumatic Brain Injury. J Neurotrauma 2020; 37:924-938. [PMID: 31650880 DOI: 10.1089/neu.2019.6739] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Traumatic brain injury (TBI) causes damage to the hypothalamo-hypophyseal axis, leading to endocrine dysregulation in up to 40% of TBI patients. Hence, there is an urgent need to identify non-invasive biomarkers for TBI-associated hypothalamo-hypophyseal pathology. Sushi repeat-containing protein X-linked 2 (SRPX2) is a novel hypothalamic protein expressed in both rat and human brain. Our objective was to investigate the effect of acquired brain injury on plasma SRPX2 protein levels and SRPX2 expression in the brain. We induced severe lateral fluid-percussion injury in adult male rats and investigated changes in SRPX2 expression at 2 h, 6 h, 24 h, 48 h, 72 h, 5 days, 7 days, 14 days, 1 month, and 3 months post-injury. The plasma SRPX2 level was assessed by Western blot analysis. Hypothalamic SRPX2-immunoreactive neuronal numbers were estimated from immunostained preparations. At 2 h post-TBI, plasma SRPX2 levels were markedly decreased compared with the naïve group (area under the curve = 1.00, p < 0.05). Severe TBI caused a reduction in the number of hypothalamic SRPX2-immunoreactive neurons bilaterally at 2 h post-TBI compared with naïve group (5032 ± 527 vs. 9440 ± 351, p < 0.05). At 1 month after severe TBI, however, the brain and plasma SRPX2 levels were comparable between the TBI and naïve groups (p > 0.05). Unsupervised hierarchical clustering using SRPX2 expression differentiated animals into injured and uninjured clusters. Our findings indicate that TBI leads to an acute reduction in SRPX2 protein expression and reduced plasma SRPX2 level may serve as a candidate biomarker of hypothalamic injury.
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Affiliation(s)
- Mehwish Anwer
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | | | - Jenni Karttunen
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | | | - Noora Puhakka
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Asla Pitkänen
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
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15
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The blockade of corticotropin-releasing factor 1 receptor attenuates anxiety-related symptoms and hypothalamus-pituitary-adrenal axis reactivity in mice with mild traumatic brain injury. Behav Pharmacol 2020; 30:220-228. [PMID: 30883392 DOI: 10.1097/fbp.0000000000000450] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Recent studies have shown that mild traumatic brain injury (mTBI) is associated with higher risk for anxiety-related disorders. Dysregulation in the hypothalamus-pituitary-adrenal (HPA) axis following mTBI has been proposed to be involved in the development of neurobehavioral abnormalities; however, the underlying mechanisms are largely unknown. The aim of this study was to determine whether the corticotropin-releasing-factor-1 (CRF-1) receptor is involved in the regulation of anxiety-related symptoms in a mouse model of mTBI. Animals with or without mTBI received intracerebroventricular injections of a CRF-1 receptor agonist (CRF; 0.01 nmol/mouse) or antagonist (antalarmin; 1 µg/mouse) for 5 days, and then the animals were subjected to anxiety tests (light-dark box and zero maze). The levels of adrenocorticotropic hormone and corticosterone, the most important markers of HPA axis, were also measured after behavioral tests. Our results indicated that mTBI-induced anxiety-related symptoms in mice through increased levels of adrenocorticotropic hormone and corticosterone, showing HPA axis hyperactivity. Interestingly, activation of CRF receptor by a subthreshold dose of CRF resulted in significant increases in anxiety-like behaviors and HPA axis response to stress, whereas blockade of CRF receptors by a subthreshold dose of antalarmin decreased anxiety-related symptoms and HPA axis response to stress in mTBI-induced mice. Collectively, these findings suggest that the CRF-1 receptor plays an important role in the regulation of anxiety-related behaviors following mTBI induction in mice and support the hypothesis that blockade of the CRF-1 receptor may be a promising therapeutic target for anxiety-related disorders in patients with TBI.
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16
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Stress reactivity after traumatic brain injury: implications for comorbid post-traumatic stress disorder. Behav Pharmacol 2020; 30:115-121. [PMID: 30640181 DOI: 10.1097/fbp.0000000000000461] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Most people have or will experience traumatic stress at some time over the lifespan, but only a subset of traumatized individuals develop post-traumatic stress disorder (PTSD). Clinical research supports high rates of traumatic brain injury (TBI)-PTSD comorbidity and demonstrates TBI as a significant predictor of the development of PTSD. Biological factors impacted following brain injury that may contribute to increased PTSD risk are unknown. Heightened stress reactivity and dysregulated hypothalamic-pituitary-adrenal (HPA) axis function are common to both TBI and PTSD, and affect amygdalar structure and function, which is implicated in PTSD. In this review, we summarize a growing body of literature that shows HPA axis dysregulation, as well as enhanced fear and amygdalar function after TBI. We present the hypothesis that altered stress reactivity as a result of brain injury impacts the amygdala and defense systems to be vulnerable to increased fear and PTSD development from traumatic stress. Identifying biological mechanisms that underlie this vulnerability, such as dysregulated HPA axis function, may lead to better targeted treatments and preventive measures to support psychological health after TBI.
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17
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Anwer M, Immonen R, Hayward NMEA, Ndode-Ekane XE, Puhakka N, Gröhn O, Pitkänen A. Lateral fluid-percussion injury leads to pituitary atrophy in rats. Sci Rep 2019; 9:11819. [PMID: 31413303 PMCID: PMC6694150 DOI: 10.1038/s41598-019-48404-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 08/02/2019] [Indexed: 12/26/2022] Open
Abstract
Traumatic brain injury (TBI) causes neuroendocrine dysregulation in up to 40% of humans, which is related to impaired function of the hypothalamo-hypophyseal axis and contributes to TBI-related co-morbidities. Our objective was to investigate whether hypophyseal atrophy can be recapitulated in rat lateral fluid-percussion injury model of human TBI. High-resolution structural magnetic resonance images (MRI) were acquired from rats at 2 days and 5 months post-TBI. To measure the lobe-specific volumetric changes, manganese-enhanced MRI (MEMRI) scans were acquired from rats at 8 months post-TBI, which also underwent the pentylenetetrazol (PTZ) seizure susceptibility and Morris water-maze spatial memory tests. MRI revealed no differences in the total hypophyseal volume between TBI and controls at 2 days, 5 months or 8 months post-TBI. Surprisingly, MEMRI at 8 months post-TBI indicated a 17% reduction in neurohypophyseal volume in the TBI group as compared to controls (1.04 ± 0.05 mm3 vs 1.25 ± 0.05 mm3, p < 0.05). Moreover, neurohypophyseal volume inversely correlated with the number of PTZ-induced epileptiform discharges and the mean latency to platform in the Morris water-maze test. Our data demonstrate that TBI leads to neurohypophyseal lobe-specific atrophy and may serve as a prognostic biomarker for post-TBI outcome.
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Affiliation(s)
- Mehwish Anwer
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Riikka Immonen
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Nick M E A Hayward
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | | | - Noora Puhakka
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Olli Gröhn
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Asla Pitkänen
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
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18
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Vennekens A, Vankelecom H. Traumatic brain injury and resultant pituitary dysfunction: insights from experimental animal models. Pituitary 2019; 22:212-219. [PMID: 31020506 DOI: 10.1007/s11102-019-00961-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
PURPOSE Traumatic brain injury (TBI) is a major worldwide cause of disability, often burdening young people with serious lifelong health problems. A frequent clinical complication is post-traumatic hypopituitarism (PTHP) manifesting in several hypothalamus-pituitary axes. The head trauma-induced mechanisms underlying PTHP remain largely unknown. Several hypotheses have been proposed including direct damage to the pituitary gland and hypothalamus, vascular events and autoimmunity. This review aims to provide a summary of the currently limited number of studies exploring hypothalamus-pituitary dysfunction in experimental animal TBI models. RESULTS Although the impact of different forms of TBI on a number of hypothalamus-pituitary axes has been investigated, consequences for pituitary tissue and function have only scarcely been described. Moreover, mechanisms underlying the endocrine dysfunctions remain under explored. CONCLUSIONS Studies on TBI-induced pituitary dysfunction are still scarce. More research is needed to acquire mechanistic insights into the pathophysiology of PTHP which may eventually open up the horizon toward better treatments, including pituitary-regenerative approaches.
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Affiliation(s)
- Annelies Vennekens
- Department of Development and Regeneration, Cluster of Stem Cell and Developmental Biology, Unit of Stem Cell Research, KU Leuven (University of Leuven), Campus Gasthuisberg O&N4, Herestraat 49, 3000, Leuven, Belgium
| | - Hugo Vankelecom
- Department of Development and Regeneration, Cluster of Stem Cell and Developmental Biology, Unit of Stem Cell Research, KU Leuven (University of Leuven), Campus Gasthuisberg O&N4, Herestraat 49, 3000, Leuven, Belgium.
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19
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Gan ZS, Stein SC, Swanson R, Guan S, Garcia L, Mehta D, Smith DH. Blood Biomarkers for Traumatic Brain Injury: A Quantitative Assessment of Diagnostic and Prognostic Accuracy. Front Neurol 2019; 10:446. [PMID: 31105646 PMCID: PMC6498532 DOI: 10.3389/fneur.2019.00446] [Citation(s) in RCA: 105] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 04/12/2019] [Indexed: 12/18/2022] Open
Abstract
Blood biomarkers have been explored for their potential to provide objective measures in the assessment of traumatic brain injury (TBI). However, it is not clear which biomarkers are best for diagnosis and prognosis in different severities of TBI. Here, we compare existing studies on the discriminative abilities of serum biomarkers for four commonly studied clinical situations: detecting concussion, predicting intracranial damage after mild TBI (mTBI), predicting delayed recovery after mTBI, and predicting adverse outcome after severe TBI (sTBI). We conducted a literature search of publications on biomarkers in TBI published up until July 2018. Operating characteristics were pooled for each biomarker for comparison. For detecting concussion, 4 biomarker panels and creatine kinase B type had excellent discriminative ability. For detecting intracranial injury and the need for a head CT scan after mTBI, 2 biomarker panels, and hyperphosphorylated tau had excellent operating characteristics. For predicting delayed recovery after mTBI, top candidates included calpain-derived αII-spectrin N-terminal fragment, tau A, neurofilament light, and ghrelin. For predicting adverse outcome following sTBI, no biomarker had excellent performance, but several had good performance, including markers of coagulation and inflammation, structural proteins in the brain, and proteins involved in homeostasis. The highest-performing biomarkers in each of these categories may provide insight into the pathophysiologies underlying mild and severe TBI. With further study, these biomarkers have the potential to be used alongside clinical and radiological data to improve TBI diagnostics, prognostics, and evidence-based medical management.
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Affiliation(s)
- Zoe S Gan
- University of North Carolina School of Medicine, Chapel Hill, NC, United States
| | - Sherman C Stein
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Randel Swanson
- Department of Physical Medicine and Rehabilitation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.,Rehabilitation Medicine Service, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, United States.,Center for Neurotrauma, Neurodegeneration and Restoration, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, United States.,Department of Neurosurgery, Perelman School of Medicine, Center for Brain Injury and Repair, University of Pennsylvania, Philadelphia, PA, United States
| | - Shaobo Guan
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Lizette Garcia
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Devanshi Mehta
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Douglas H Smith
- Department of Neurosurgery, Perelman School of Medicine, Center for Brain Injury and Repair, University of Pennsylvania, Philadelphia, PA, United States
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Tapp ZM, Godbout JP, Kokiko-Cochran ON. A Tilted Axis: Maladaptive Inflammation and HPA Axis Dysfunction Contribute to Consequences of TBI. Front Neurol 2019; 10:345. [PMID: 31068886 PMCID: PMC6491704 DOI: 10.3389/fneur.2019.00345] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 03/20/2019] [Indexed: 12/16/2022] Open
Abstract
Each year approximately 1.7 million people sustain a traumatic brain injury (TBI) in the US alone. Associated with these head injuries is a high prevalence of neuropsychiatric symptoms including irritability, depression, and anxiety. Neuroinflammation, due in part to microglia, can worsen or even cause neuropsychiatric disorders after TBI. For example, mounting evidence demonstrates that microglia become “primed” or hyper-reactive with an exaggerated pro-inflammatory phenotype following multiple immune challenges. Microglial priming occurs after experimental TBI and correlates with the emergence of depressive-like behavior as well as cognitive dysfunction. Critically, immune challenges are various and include illness, aging, and stress. The collective influence of any combination of these immune challenges shapes the neuroimmune environment and the response to TBI. For example, stress reliably induces inflammation and could therefore be a gateway to altered neuropathology and behavioral decline following TBI. Given the increasing incidence of stress-related psychiatric disorders after TBI, the degree in which stress affects outcome is of particular interest. This review aims to highlight the role of the hypothalamic-pituitary-adrenal (HPA) axis as a key mediator of stress-immune pathway communication following TBI. We will first describe maladaptive neuroinflammation after TBI and how stress contributes to inflammation through both anti- and pro-inflammatory mechanisms. Clinical and experimental data describing HPA-axis dysfunction and consequences of altered stress responses after TBI will be discussed. Lastly, we will review common stress models used after TBI that could better elucidate the relationship between HPA axis dysfunction and maladaptive inflammation following TBI. Together, the studies described in this review suggest that HPA axis dysfunction after brain injury is prevalent and contributes to the dynamic nature of the neuroinflammatory response to brain injury. Experimental stressors that directly engage the HPA axis represent important areas for future research to better define the role of stress-immune pathways in mediating outcome following TBI.
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Affiliation(s)
- Zoe M Tapp
- Department of Neuroscience, Institute for Behavioral Medicine Research, College of Medicine, The Ohio State University, Columbus, OH, United States
| | - Jonathan P Godbout
- Department of Neuroscience, Institute for Behavioral Medicine Research, College of Medicine, The Ohio State University, Columbus, OH, United States
| | - Olga N Kokiko-Cochran
- Department of Neuroscience, Institute for Behavioral Medicine Research, College of Medicine, The Ohio State University, Columbus, OH, United States
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Tanaka H, Ehara A, Nakadate K, Yoshimoto K, Shimoda K, Ueda S. Behavioral, hormonal, and neurochemical outcomes of neonatal repeated shaking brain injury in male adult rats. Physiol Behav 2019; 199:118-126. [DOI: 10.1016/j.physbeh.2018.11.025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Revised: 11/03/2018] [Accepted: 11/18/2018] [Indexed: 12/18/2022]
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de la Tremblaye PB, O'Neil DA, LaPorte MJ, Cheng JP, Beitchman JA, Thomas TC, Bondi CO, Kline AE. Elucidating opportunities and pitfalls in the treatment of experimental traumatic brain injury to optimize and facilitate clinical translation. Neurosci Biobehav Rev 2018; 85:160-175. [PMID: 28576511 PMCID: PMC5709241 DOI: 10.1016/j.neubiorev.2017.05.022] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 05/12/2017] [Indexed: 12/19/2022]
Abstract
The aim of this review is to discuss the research presented in a symposium entitled "Current progress in characterizing therapeutic strategies and challenges in experimental CNS injury" which was presented at the 2016 International Behavioral Neuroscience Society annual meeting. Herein we discuss diffuse and focal traumatic brain injury (TBI) and ensuing chronic behavioral deficits as well as potential rehabilitative approaches. We also discuss the effects of stress on executive function after TBI as well as the response of the endocrine system and regulatory feedback mechanisms. The role of the endocannabinoids after CNS injury is also discussed. Finally, we conclude with a discussion of antipsychotic and antiepileptic drugs, which are provided to control TBI-induced agitation and seizures, respectively. The review consists predominantly of published data.
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Affiliation(s)
- Patricia B de la Tremblaye
- Department of Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, PA, United States; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, United States
| | - Darik A O'Neil
- Department of Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, PA, United States; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, United States
| | - Megan J LaPorte
- Department of Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, PA, United States; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, United States
| | - Jeffrey P Cheng
- Department of Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, PA, United States; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, United States
| | - Joshua A Beitchman
- Barrow Neurological Institute at Phoenix Children's Hospital, Phoenix, AZ, United States; Department of Child Health, University of Arizona College of Medicine, Phoenix, AZ, United States; Midwestern University, Glendale, AZ, United States
| | - Theresa Currier Thomas
- Barrow Neurological Institute at Phoenix Children's Hospital, Phoenix, AZ, United States; Department of Child Health, University of Arizona College of Medicine, Phoenix, AZ, United States; Phoenix VA Healthcare System, Phoenix, AZ, United States
| | - Corina O Bondi
- Department of Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, PA, United States; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, United States; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, United States; Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, United States
| | - Anthony E Kline
- Department of Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, PA, United States; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, United States; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, United States; Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, PA, United States; Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States; Department of Psychology, University of Pittsburgh, Pittsburgh, PA, United States.
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Assessment of the role of intracranial hypertension and stress on hippocampal cell apoptosis and hypothalamic-pituitary dysfunction after TBI. Sci Rep 2017. [PMID: 28630478 PMCID: PMC5476648 DOI: 10.1038/s41598-017-04008-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
In recent years, hypopituitarism caused by traumatic brain injury (TBI) has been explored in many clinical studies; however, few studies have focused on intracranial hypertension and stress caused by TBI. In this study, an intracranial hypertension model, with epidural hematoma as the cause, was used to explore the physiopathological and neuroendocrine changes in the hypothalamic-pituitary axis and hippocampus. The results demonstrated that intracranial hypertension increased the apoptosis rate, caspase-3 levels and proliferating cell nuclear antigen (PCNA) in the hippocampus, hypothalamus, pituitary gland and showed a consistent rate of apoptosis within each group. The apoptosis rates of hippocampus, hypothalamus and pituitary gland were further increased when intracranial pressure (ICP) at 24 hour (h) were still increased. The change rates of apoptosis in hypothalamus and pituitary gland were significantly higher than hippocampus. Moreover, the stress caused by surgery may be a crucial factor in apoptosis. To confirm stress leads to apoptosis in the hypothalamus and pituitary gland, we used rabbits to establish a standard stress model. The results confirmed that stress leads to apoptosis of neuroendocrine cells in the hypothalamus and pituitary gland, moreover, the higher the stress intensity, the higher the apoptosis rate in the hypothalamus and pituitary gland.
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Lifshitz J, Rowe RK, Griffiths DR, Evilsizor MN, Thomas TC, Adelson PD, McIntosh TK. Clinical relevance of midline fluid percussion brain injury: Acute deficits, chronic morbidities and the utility of biomarkers. Brain Inj 2016; 30:1293-1301. [PMID: 27712117 DOI: 10.1080/02699052.2016.1193628] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND After 30 years of characterisation and implementation, fluid percussion injury (FPI) is firmly recognised as one of the best-characterised reproducible and clinically relevant models of TBI, encompassing concussion through diffuse axonal injury (DAI). Depending on the specific injury parameters (e.g. injury site, mechanical force), FPI can model diffuse TBI with or without a focal component and may be designated as mild-to-severe according to the chosen mechanical forces and resulting acute neurological responses. Among FPI models, midline FPI may best represent clinical diffuse TBI, because of the acute behavioural deficits, the transition to late-onset behavioural morbidities and the absence of gross histopathology. REVIEW The goal here was to review acute and chronic physiological and behavioural deficits and morbidities associated with diffuse TBI induced by midline FPI. In the absence of neurodegenerative sequelae associated with focal injury, there is a need for biomarkers in the diagnostic, prognostic, predictive and therapeutic approaches to evaluate outcomes from TBI. CONCLUSIONS The current literature suggests that midline FPI offers a clinically-relevant, validated model of diffuse TBI to investigators wishing to evaluate novel therapeutic strategies in the treatment of TBI and the utility of biomarkers in the delivery of healthcare to patients with brain injury.
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Affiliation(s)
- Jonathan Lifshitz
- a Translational Neurotrauma Research Program , BARROW Neurological Institute at Phoenix Children's Hospital , Phoenix , AZ , USA.,b Department of Child Health , University of Arizona, College of Medicine - Phoenix , Phoenix , AZ , USA.,c Phoenix VA Healthcare System , Phoenix , AZ , USA.,d Neuroscience Graduate Program , Arizona State University , Tempe , AZ , USA
| | - Rachel K Rowe
- a Translational Neurotrauma Research Program , BARROW Neurological Institute at Phoenix Children's Hospital , Phoenix , AZ , USA.,b Department of Child Health , University of Arizona, College of Medicine - Phoenix , Phoenix , AZ , USA.,c Phoenix VA Healthcare System , Phoenix , AZ , USA
| | - Daniel R Griffiths
- a Translational Neurotrauma Research Program , BARROW Neurological Institute at Phoenix Children's Hospital , Phoenix , AZ , USA.,b Department of Child Health , University of Arizona, College of Medicine - Phoenix , Phoenix , AZ , USA
| | - Megan N Evilsizor
- a Translational Neurotrauma Research Program , BARROW Neurological Institute at Phoenix Children's Hospital , Phoenix , AZ , USA.,b Department of Child Health , University of Arizona, College of Medicine - Phoenix , Phoenix , AZ , USA
| | - Theresa C Thomas
- a Translational Neurotrauma Research Program , BARROW Neurological Institute at Phoenix Children's Hospital , Phoenix , AZ , USA.,b Department of Child Health , University of Arizona, College of Medicine - Phoenix , Phoenix , AZ , USA.,c Phoenix VA Healthcare System , Phoenix , AZ , USA.,d Neuroscience Graduate Program , Arizona State University , Tempe , AZ , USA
| | - P David Adelson
- a Translational Neurotrauma Research Program , BARROW Neurological Institute at Phoenix Children's Hospital , Phoenix , AZ , USA.,b Department of Child Health , University of Arizona, College of Medicine - Phoenix , Phoenix , AZ , USA.,d Neuroscience Graduate Program , Arizona State University , Tempe , AZ , USA
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25
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Hoffman AN, Paode PR, May HG, Ortiz JB, Kemmou S, Lifshitz J, Conrad CD, Currier Thomas T. Early and Persistent Dendritic Hypertrophy in the Basolateral Amygdala following Experimental Diffuse Traumatic Brain Injury. J Neurotrauma 2016; 34:213-219. [PMID: 27306143 DOI: 10.1089/neu.2015.4339] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
In the pathophysiology of traumatic brain injury (TBI), the amygdala remains understudied, despite involvement in processing emotional and stressful stimuli associated with anxiety disorders, such as post-traumatic stress disorder (PTSD). Because the basolateral amygdala (BLA) integrates inputs from sensory and other limbic structures coordinating emotional learning and memory, injury-induced changes in circuitry may contribute to psychiatric sequelae of TBI. This study quantified temporal changes in dendritic complexity of BLA neurons after experimental diffuse TBI, modeled by midline fluid percussion injury. At post-injury days (PIDs) 1, 7, and 28, brain tissue from sham and brain-injured adult, male rats was processed for Golgi, glial fibrillary acidic protein (GFAP), or silver stain and analyzed to quantify BLA dendritic branch intersections, activated astrocytes, and regional neuropathology, respectively. Compared to sham, brain-injured rats at all PIDs showed enhanced dendritic branch intersections in both pyramidal and stellate BLA neuronal types, as evidenced by Sholl analysis. GFAP staining in the BLA was significantly increased at PID1 and 7 in comparison to sham. However, the BLA was relatively spared from neuropathology, demonstrated by an absence of argyrophilic accumulation over time, in contrast to other brain regions. These data suggest an early and persistent enhancement of dendritic complexity within the BLA after a single diffuse TBI. Increased dendritic complexity would alter information processing into and through the amygdala, contributing to emotional symptoms post-TBI, including PTSD.
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Affiliation(s)
- Ann N Hoffman
- 1 Department of Psychology, Arizona State University , Tempe, Arizona.,5 Department of Psychology, UCLA , Los Angeles, California.,6 Brain Injury Research Center, Department of Neurosurgery, David Geffen School of Medicine at UCLA , Los Angeles, California
| | - Pooja R Paode
- 1 Department of Psychology, Arizona State University , Tempe, Arizona
| | - Hazel G May
- 2 Department of Child Health, University of Arizona College of Medicine-Phoenix , Phoenix, Arizona.,3 Barrow Neurological Institute at Phoenix Children's Hospital , Phoenix, Arizona.,7 Department of Biology and Biochemistry, University of Bath , Bath, United Kingdom
| | - J Bryce Ortiz
- 1 Department of Psychology, Arizona State University , Tempe, Arizona
| | - Salma Kemmou
- 1 Department of Psychology, Arizona State University , Tempe, Arizona
| | - Jonathan Lifshitz
- 1 Department of Psychology, Arizona State University , Tempe, Arizona.,2 Department of Child Health, University of Arizona College of Medicine-Phoenix , Phoenix, Arizona.,3 Barrow Neurological Institute at Phoenix Children's Hospital , Phoenix, Arizona.,4 Phoenix VA Healthcare System , Phoenix, Arizona
| | - Cheryl D Conrad
- 1 Department of Psychology, Arizona State University , Tempe, Arizona
| | - Theresa Currier Thomas
- 2 Department of Child Health, University of Arizona College of Medicine-Phoenix , Phoenix, Arizona.,3 Barrow Neurological Institute at Phoenix Children's Hospital , Phoenix, Arizona.,4 Phoenix VA Healthcare System , Phoenix, Arizona
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26
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Tanriverdi F, Schneider HJ, Aimaretti G, Masel BE, Casanueva FF, Kelestimur F. Pituitary dysfunction after traumatic brain injury: a clinical and pathophysiological approach. Endocr Rev 2015; 36:305-42. [PMID: 25950715 DOI: 10.1210/er.2014-1065] [Citation(s) in RCA: 127] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Traumatic brain injury (TBI) is a growing public health problem worldwide and is a leading cause of death and disability. The causes of TBI include motor vehicle accidents, which are the most common cause, falls, acts of violence, sports-related head traumas, and war accidents including blast-related brain injuries. Recently, pituitary dysfunction has also been described in boxers and kickboxers. Neuroendocrine dysfunction due to TBI was described for the first time in 1918. Only case reports and small case series were reported until 2000, but since then pituitary function in TBI victims has been investigated in more detail. The frequency of hypopituitarism after TBI varies widely among different studies (15-50% of the patients with TBI in most studies). The estimates of persistent hypopituitarism decrease to 12% if repeated testing is applied. GH is the most common hormone lost after TBI, followed by ACTH, gonadotropins (FSH and LH), and TSH. The underlying mechanisms responsible for pituitary dysfunction after TBI are not entirely clear; however, recent studies have shown that genetic predisposition and autoimmunity may have a role. Hypopituitarism after TBI may have a negative impact on the pace or degree of functional recovery and cognition. What is not clear is whether treatment of hypopituitarism has a beneficial effect on specific function. In this review, the current data related to anterior pituitary dysfunction after TBI in adult patients are updated, and guidelines for the diagnosis, follow-up strategies, and therapeutic approaches are reported.
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Affiliation(s)
- Fatih Tanriverdi
- Erciyes University Medical School (F.T., F.K.), Department of Endocrinology, 38039 Kayseri, Turkey
| | - Harald Jörn Schneider
- Medizinische Klinik und Poliklinik IV (H.J.S.), Ludwig-Maximilians University, 80539 Munich, Germany
| | - Gianluca Aimaretti
- Department of Translational Medicine (G.A.), University “A. Avogadro” of the Eastern Piedmont, University Hospital Maggiore della Carità, 28100 Novara, Italy
| | - Brent E. Masel
- Department of Neurology (B.E.M.), Transitional Learning Center at Galveston, The Moody Center for Traumatic Brain & Spinal Cord Injury Research/Mission Connect, The University of Texas Medical Branch, Galveston, Texas 77550
| | - Felipe F. Casanueva
- Faculty of Medicine (F.F.C.), Santiago de Compostela University, Complejo Hospitalario Universitario de Santiago; CIBER de Fisiopatologia Obesidad y Nutricion, Instituto Salud Carlos III, Santiago de Compostela 15782, Spain
| | - Fahrettin Kelestimur
- Erciyes University Medical School (F.T., F.K.), Department of Endocrinology, 38039 Kayseri, Turkey
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27
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Keshavarzi Z, Khaksari M. The effects of female sexual steroids on gastric function and barrier resistance of gastrointestinal tract following traumatic brain injury. J Pharm Bioallied Sci 2015; 7:75-80. [PMID: 25709342 PMCID: PMC4333633 DOI: 10.4103/0975-7406.149815] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Revised: 07/29/2014] [Accepted: 09/02/2014] [Indexed: 11/04/2022] Open
Abstract
AIM The aim was to assess the alteration of gastric function and barrier function of gastrointestinal (GI) tract following diffuse brain injury in varying ovarian hormone status. MATERIALS AND METHODS Diffuse traumatic brain injury (TBI) was induced by Marmarou method. Rats were randomly assigned into 10 groups: Intact, sham + ovariectomized female (OVX), TBI, TBI + OVX, vehicle, estradiol (E2), progesterone (P), E2 + P, estrogen receptor alpha agonist and estrogen receptor beta agonist (DPN). Endotoxin levels were measured using enzyme-linked immunosorbent assay method. All the parameters were measured 5 days after TBI. RESULTS Intragastric pressure was significantly decreased in TBI as compared to the intact group (P < 0.001) and this was lower in TBI group versus TBI + OVX group (P < 0.05). Pretreatment with steroid hormones and their agonists did not have any effect on the gastric pressure compared to TBI + OVX or vehicle groups. Inflammation, congestion, ulcer and erosion were seen in the TBI rats. All treatment groups worsen the tissue condition so that the presence of thrombosis also was seen. The trauma induction did not have any effect on the serum and intestinal endotoxin levels. DPN had caused a significant reduction in serum levels of endotoxin compared with OVX + TBI group (P < 0.05). CONCLUSION Pretreatment with sexual steroids is not useful in the treatment of GI dysfunction induced by TBI. The treatment with all sexual female hormones worsens the gastric tissue condition. Furthermore, the applied weight was not enough for releasing of endotoxin. It seems that estrogen reduced the endotoxin levels by estrogen beta receptor.
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Affiliation(s)
- Zakieh Keshavarzi
- Departments Physiology, Bojnurd University of Medical Sciences, Bojnurd, Iran
| | - Mohammad Khaksari
- Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran
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Ellis TW, Ziebell JM, David Adelson P, Lifshitz J. Commentary on Kamper et. al., juvenile traumatic brain injury evolves into a chronic brain disorder: The challenges in longitudinal studies of juvenile traumatic brain injury. Exp Neurol 2014; 261:434-9. [DOI: 10.1016/j.expneurol.2014.06.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Revised: 06/02/2014] [Accepted: 06/06/2014] [Indexed: 10/25/2022]
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Xu Z, Lv XA, Wang JW, Chen ZP, Qiu HS. Predictive value of early decreased plasma ghrelin level for three-month cognitive deterioration in patients with mild traumatic brain injury. Peptides 2014; 54:180-5. [PMID: 24508379 DOI: 10.1016/j.peptides.2014.01.021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2013] [Revised: 01/25/2014] [Accepted: 01/25/2014] [Indexed: 11/29/2022]
Abstract
The orexigenic hormone, ghrelin, is tightly linked to cognition impairment in neurodegenerative disorders. No previous studies have investigated the early ghrelin concentration change in patients with mild traumatic brain injury (mTBI) and it's relationship to cognitive deterioration. This study was performed to investigate the early plasma ghrelin concentrations in patients with mTBI and to explore the relationship between ghrelin and cognitive deterioration. Plasma ghrelin concentrations of 118 adults after acute mTBI were determined by enzyme-linked immunosorbent assay. Forty patients (33.9%) had cognitive deterioration three months after mTBI. Plasma ghrelin levels were significantly lower in mTBI patients with cognitive deterioration than patients without cognitive deterioration (38.8±4.5 pg/mL vs 50.8±7.7 pg/mL, P<0.001). Decreased Plasma ghrelin level was identified as an independent predictor for three-month cognitive deterioration after mTBI (odds ratio, 0.746; 95% confidence interval, 0.651-0.856; P<0.001). Plasma ghrelin level was negatively associated with serum adrenocorticotrophin hormone level (t=-6.854, P<0.001) and age (t=-6.112, P<0.001). A plasma ghrelin level of 41.6 pg/mL predicted three-month cognitive deterioration after mTBI with the optimal sensitivity (85.9%) and specificity (80.0%) values (area under curve, 0.904; 95% confidence interval, 0.852-0.957; P<0.001). The predictive value of ghrelin was bigger than that of serum adrenocorticotrophin hormone level (area under curve, 0.638; 95% confidence interval, 0.536-0.741; P=0.014) and age (area under curve, 0.638; 95% confidence interval, 0.536-0.741; P=0.014) for three-month cognitive deterioration after mTBI.
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Affiliation(s)
- Zhen Xu
- Department of Neurosurgery, First Affiliated Hospital of Zhejiang Chinese Medicine University, 54 Youdian Lane, Hangzhou 310006, China.
| | - Xiao-Ai Lv
- Department of Surgery, First Affiliated Hospital of Zhejiang Chinese Medicine University, 54 Youdian Lane, Hangzhou 310006, China
| | - Ji-Wei Wang
- Department of Neurosurgery, Affiliated Hospital of Hebei University, 212 Yuhua East Lane, Baoding 071000, China
| | - Zu-Peng Chen
- Department of Neurosurgery, First Affiliated Hospital of Zhejiang Chinese Medicine University, 54 Youdian Lane, Hangzhou 310006, China
| | - Hua-Sen Qiu
- Department of Surgery, First Affiliated Hospital of Zhejiang Chinese Medicine University, 54 Youdian Lane, Hangzhou 310006, China
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Taylor AN, Tio DL, Sutton RL. Restoration of neuroendocrine stress response by glucocorticoid receptor or GABA(A) receptor antagonists after experimental traumatic brain injury. J Neurotrauma 2013; 30:1250-6. [PMID: 23384619 PMCID: PMC3713445 DOI: 10.1089/neu.2012.2847] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
We previously reported that traumatic brain injury (TBI) produced by moderate controlled cortical impact (CCI) attenuates the stress response of the hypothalamic-pituitary-adrenal (HPA) axis between 21 and 70 days postinjury and enhances the sensitivity of the stress response to glucocorticoid negative feedback. In the current study, we investigated two possible mechanisms for the CCI-induced attenuation of the HPA stress response-i.e, glucocorticoid receptor (GR) and GABA-mediated inhibition of the HPA axis, with the GR antagonist, mifepristone (RU486), or the GABA(A)-receptor antagonist, bicuculline. In addition, we examined the effect of moderate CCI on GR and inhibitory neurons histologically in subfields of the hippocampus, medial prefrontal cortex, and amygdala. We show that at 30-min after onset of restraint stress, GR as well as GABA antagonism with MIFE or BIC, respectively, reversed the attenuating effects of moderate CCI on the stress-induced HPA response. Our histological results demonstrate that moderate CCI led to a loss of glutamic acid decarboxylase 67 or parvalbumin-positive inhibitory neurons within regions of the hippocampus and amygdala but did not lead to significant increases in GR in these regions. These findings indicate that suppression of the stress-induced HPA response after moderate CCI is mediated by the inhibitory actions of both GR and GABA, with a corresponding loss of inhibitory neurons within brain regions with neural pathways affecting limbic stress-integrative pathways.
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Affiliation(s)
- Anna N Taylor
- Department of Neurobiology, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Box 951763, Los Angeles, CA 90095-1763, USA.
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Abstract
Mild traumatic brain injury, especially sport-related concussion, is common among young persons. Consequences of transient pathophysiologic dysfunction must be considered in the context of a developing or immature brain, as must the potential for an accumulation of damage with repeated exposure. This review summarizes the underlying neurometabolic cascade of concussion, with emphasis on the young brain in terms of acute pathophysiology, vulnerability, alterations in plasticity and activation, axonal injury, and cumulative risk from chronic, repetitive damage, and discusses their implications in the context of clinical care for the concussed youth, highlighting areas for future investigation.
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Affiliation(s)
- Daniel W Shrey
- Division of Pediatric Neurology, Department of Pediatrics, David Geffen School of Medicine at UCLA, Mattel Children's Hospital, Los Angeles, CA 90095, USA.
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Griesbach GS, Hovda DA, Tio DL, Taylor AN. Heightening of the stress response during the first weeks after a mild traumatic brain injury. Neuroscience 2011; 178:147-58. [PMID: 21277947 DOI: 10.1016/j.neuroscience.2011.01.028] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2010] [Revised: 01/11/2011] [Accepted: 01/13/2011] [Indexed: 11/18/2022]
Abstract
The effects of a mild traumatic brain injury range from white matter disruption to affective disorders. We set out to determine the response to restraint-induced stress after a mild fluid-percussion injury (FPI), an experimental model for brain injury. Hypothalamic-pituitary-adrenal (HPA) axis regulation of corticosterone (CORT) and adrenocorticotropic hormone (ACTH) was determined during the first post-injury weeks, which corresponds to the same time period when rehabilitative exercise has been shown to be ineffective after a mild FPI. Adult male rats underwent either an FPI or sham injury. Additional rats were only exposed to anesthesia. HPA regulation was evaluated by measuring the effects of dexamethasone (DEX) treatment on CORT and ACTH. Tail vein blood was collected following 30-min restraint stress, at post-injury days (PID) 1, 7 and 14, prior to (0 min) and at 30, 60, 90 and 120 min after stress onset. Results from these studies indicate that the stress response was significantly more pronounced after FPI in that CORT and ACTH restraint-induced increases were more pronounced and longer lasting compared to controls. DEX suppression of CORT and ACTH was observed in all groups, suggesting that stress hyper-responsiveness after mild FPI is not attributable to reduced sensitivity of CORT feedback regulation. The increased sensitivity to stressful events in the first two post-injury weeks after a mild FPI may have a negative impact on early rehabilitative therapies.
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Affiliation(s)
- G S Griesbach
- Department of Neurosurgery, David Geffen School of Medicine at University of California Los Angeles, Box 957030, Los Angeles, CA 90095-7039, USA.
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Taylor AN, Rahman SU, Tio DL, Gardner SM, Kim CJ, Sutton RL. Injury severity differentially alters sensitivity to dexamethasone after traumatic brain injury. J Neurotrauma 2010; 27:1081-9. [PMID: 20560754 DOI: 10.1089/neu.2009.1252] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
We have reported differential short- and long-term dysregulation of the neuroendocrine stress response after traumatic brain injury (TBI) produced by controlled cortical impact (CCI). We have now investigated three possible mechanisms for this TBI-induced dysregulation: (1) effects on the sensitivity of negative-feedback systems to glucocorticoids; (2) effects on the sensitivity of pituitary corticotrophs to corticotropin-releasing hormone (CRH); and (3) effects on neuronal loss in the hilar region of the dentate gyrus and in the CA3b layer of the dorsal hippocampus. TBI was induced to the left parietal cortex in adult male rats with a pneumatic piston, at two different impact velocities and compression depths, to produce either moderate or mild CCI. At 7 and 35 days after surgery, the rats were injected SC with the synthetic glucocorticoid analog dexamethasone (DEX; 0.01, 0.10, or 1.00 mg/kg) or saline, and 2 h later were subjected to 30 min of restraint stress and tail vein blood collection. Whereas all doses of DEX suppressed corticosterone (CORT) and adrenocorticotropic hormone (ACTH) responses to stress on both days, CORT and ACTH were significantly more suppressed after 0.01 mg/kg DEX in the moderate TBI group than in the mild TBI or sham groups. At both 7 and 35 days post-TBI, CRH (1.0 and 10.0 microg/kg IP) stimulated CORT and ACTH in all rats, regardless of injury condition. Hippocampal cell loss was greatest at 48 days after moderate TBI. Enhanced sensitivity to glucocorticoid negative feedback and greater hippocampal cell loss, but not altered pituitary responses to CRH, contribute to the short- and long-term attenuation of the neuroendocrine stress response following moderate TBI. The role of TBI-induced alterations in glucocorticoid receptors in limbic system sites in enhanced glucocorticoid feedback sensitivity requires further investigation.
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Affiliation(s)
- Anna N Taylor
- Department of Neurobiology, Brain Research Institute and Brain Injury Research Center, David Geffen School of Medicine at UCLA, and West Los Angeles Healthcare Center, VA Greater Los Angeles Healthcare System (VAGLAHS), Los Angeles, California 90095-1763, USA.
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Fukushima M, Lee SM, Moro N, Hovda DA, Sutton RL. Metabolic and histologic effects of sodium pyruvate treatment in the rat after cortical contusion injury. J Neurotrauma 2010; 26:1095-110. [PMID: 19594384 DOI: 10.1089/neu.2008.0771] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
This study determined the effects of intraperitoneal sodium pyruvate (SP) treatment on the levels of circulating fuels and on cerebral microdialysis levels of glucose (MD(glc)), lactate (MD(lac)), and pyruvate (MD(pyr)), and the effects of SP treatment on neuropathology after left cortical contusion injury (CCI) in rats. SP injection (1000 mg/kg) 5 min after sham injury (Sham-SP) or CCI (CCI-SP) significantly increased arterial pyruvate (p < 0.005) and lactate (p < 0.001) compared to that of saline-treated rats with CCI (CCI-Sal). Serum glucose also increased significantly in CCI-SP compared to that in CCI-Sal rats (p < 0.05), but not in Sham-SP rats. MD(pyr) was not altered after CCI-Sal, whereas MD(lac) levels within the cerebral cortex significantly increased bilaterally (p < 0.05) and those for MD(glc) decreased bilaterally (p < 0.05). MD(pyr) levels increased significantly in both Sham-SP and CCI-SP rats (p < 0.05 vs. CCI-Sal) and were higher in left/injured cortex of the CCI-SP group (p < 0.05 vs. sham-SP). In CCI-SP rats the contralateral MD(lac) decreased below CCI-Sal levels (p < 0.05) and the ipsilateral MD(glc) levels exceeded those of CCI-Sal rats (p < 0.05). Rats with a single low (500 mg/kg) or high dose (1000 mg/kg) SP treatment had fewer damaged cortical cells 6 h post-CCI than did saline-treated rats (p < 0.05), but three hourly injections of SP (1000 mg/kg) were needed to significantly reduce contusion volume 2 weeks after CCI. Thus, a single intraperitoneal SP treatment increases circulating levels of three potential brain fuels, attenuates a CCI-induced reduction in extracellular glucose while increasing extracellular levels of pyruvate, but not lactate, and can attenuate cortical cell damage occurring within 6 h of injury. Enduring (2 week) neuronal protection was achieved only with multiple SP treatments within the first 2 h post-CCI, perhaps reflecting the need for additional fuel throughout the acute period of increased metabolic demands induced by CCI.
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Affiliation(s)
- Masamichi Fukushima
- Brain Injury Research Center, David Geffen School of Medicine at UCLA, Los Angeles, California 90095-7039, USA
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Papadimos TJ, Medhkour A, Yermal S. Successful use of inhaled nitric oxide to decrease intracranial pressure in a patient with severe traumatic brain injury complicated by acute respiratory distress syndrome: a role for an anti-inflammatory mechanism? Scand J Trauma Resusc Emerg Med 2009; 17:5. [PMID: 19222848 PMCID: PMC2657771 DOI: 10.1186/1757-7241-17-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2008] [Accepted: 02/17/2009] [Indexed: 11/10/2022] Open
Abstract
Use of inhaled nitric oxide in humans with traumatic brain injury and acute respiratory distress syndrome has twice previously been reported to be beneficial. Here we report a third case. We propose that INO may decrease the inflammatory response in patients with increased intracranial pressure caused by traumatic brain injury accompanied by acute respiratory distress syndrome thereby contributing to improved outcomes.
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Affiliation(s)
- Thomas J Papadimos
- Department of Anesthesiology, College of Medicine, University of Toledo, Toledo, OH 43614, USA.
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Jin W, Wang H, Ji Y, Hu Q, Yan W, Chen G, Yin H. Increased intestinal inflammatory response and gut barrier dysfunction in Nrf2-deficient mice after traumatic brain injury. Cytokine 2008; 44:135-40. [PMID: 18722136 DOI: 10.1016/j.cyto.2008.07.005] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2008] [Revised: 07/01/2008] [Accepted: 07/14/2008] [Indexed: 01/21/2023]
Abstract
AIM To explore the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in traumatic brain injury (TBI)-induced intestinal inflammatory response and gut barrier dysfunction in the mice. METHODS Wild-type Nrf2 (+/+) and Nrf2 (-/-)-deficient mice were subjected to a moderately severe weight-drop impact-acceleration head injury. We measured nuclear factor kappa B (NF-kappaB) by electrophoretic mobility shift assay (EMSA); tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) by enzyme-linked immunosorbent assay (ELISA); intercellular adhesion molecule-1 (ICAM-1) by immunohistochemistry; intestinal permeability by lactulose/mannitol (L/M) test; plasma endotoxin by chromogenic limulus amebocyte lysate test. RESULTS Intestinal levels of NF-kappaB, pro-inflammatory cytokines and ICAM-1 in Nrf2 (-/-)-deficient mice were significantly higher compared with Nrf2 (+/+) mice at 24h after TBI. Furthermore, higher intestinal permeability and plasma level of endotoxin were observed in the Nrf2 (-/-) mice compared with Nrf2 (+/+) mice. CONCLUSION Nrf2 plays an important protective role in limiting intestinal inflammatory response and gut barrier dysfunction after TBI.
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Affiliation(s)
- Wei Jin
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, PR China
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Taylor AN, Rahman SU, Sanders NC, Tio DL, Prolo P, Sutton RL. Injury Severity Differentially Affects Short- and Long-Term Neuroendocrine Outcomes of Traumatic Brain Injury. J Neurotrauma 2008; 25:311-23. [DOI: 10.1089/neu.2007.0486] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Anna N. Taylor
- Department of Neurobiology, Brain Research Institute and Brain Injury Research Center, David Geffen School of Medicine at UCLA, Los Angeles, California; and West Los Angeles Healthcare Center, Veterans Administration, Greater Los Angeles Healthcare System, Los Angeles, California
| | - Shayan U. Rahman
- Division of Neurosurgery, Department of Surgery, and Brain Injury Research Center, David Geffen School of Medicine at UCLA, Los Angeles, California
| | | | - Delia L. Tio
- Department of Neurobiology, Brain Research Institute and Brain Injury Research Center, David Geffen School of Medicine at UCLA, Los Angeles, California; and West Los Angeles Healthcare Center, Veterans Administration, Greater Los Angeles Healthcare System, Los Angeles, California
| | - Paolo Prolo
- Division of Oral Biology, UCLA School of Dentistry, Los Angeles, California
| | - Richard L. Sutton
- Division of Neurosurgery, Department of Surgery, and Brain Injury Research Center, David Geffen School of Medicine at UCLA, Los Angeles, California
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Sun J, Wang L, Shen J, Wang Z, Qian Y. Effect of propofol on mucous permeability and inflammatory mediators expression in the intestine following traumatic brain injury in rats. Cytokine 2007; 40:151-6. [DOI: 10.1016/j.cyto.2007.09.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2007] [Revised: 08/06/2007] [Accepted: 09/06/2007] [Indexed: 10/22/2022]
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Taylor AN, Rahman SU, Tio DL, Sanders MJ, Bando JK, Truong AH, Prolo P. Lasting Neuroendocrine-Immune Effects of Traumatic Brain Injury in Rats. J Neurotrauma 2006; 23:1802-13. [PMID: 17184190 DOI: 10.1089/neu.2006.23.1802] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Traumatic brain injury (TBI) is a principal cause of long-term physical, cognitive, behavioral, and social deficits in young adults, which frequently coexist with a high incidence of substance abuse disorders. However, few studies have examined the long-term effects of TBI on the neuroendocrine-immune system. TBI was induced in adult male rats under isoflurane anesthesia by cortical contusion injury with a pneumatic piston positioned stereotaxically over the left parietal cortex. Controls underwent sham surgery without injury. At 4 weeks post-injury, the plasma corticosterone response to 30-min restraint stress was significantly blunted in TBI rats compared to the sham controls. One week later, transmitters were implanted for continuous biotelemetric recording of body temperature and spontaneous locomotor activity. At 6 weeks post-injury, the febrile response to i.p. injection of the bacterial endotoxin, lipopolysaccharide (LPS; 50 microg/kg), was significantly lower in TBI than in sham rats. At 8 weeks, swimming in the forced swim test was significantly less in TBI than sham rats. At 9 weeks, rats were rendered ethanol (EtOH) dependent by feeding an EtOH-containing liquid diet for 14 days. Cosine rhythmometry analysis of circadian body temperature Midline Estimating Statistic of Rhythm (MESOR), amplitudes, and acrophases indicated differential effects of EtOH and withdrawal in the two groups. Light- and dark-phase activity analysis indicated that TBI rats were significantly more active than the sham group, and that EtOH and withdrawal differentially affected their activity. Given the extensive interactions of the neuroendocrine-immune systems, these results demonstrate that TBI produces lasting dysregulation amidst the central substrates for allostasis and circadian rhythmicity.
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Affiliation(s)
- Anna N Taylor
- Department of Neurobiology, Brain Research Institute and Brain Injury Research Center, David Geffen School of Medicine at UCLA, West Los Angeles Healthcare Center, Los Angeles, California 90095-1763, USA.
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Aydin S, Ulusoy H, Usul H, Yulug E, Cobanoglu U, Aydin K, Yenilmez E, Kutun S. Effects of Early Versus Delayed Nutrition on Intestinal Mucosal Apoptosis and Atrophy After Traumatic Brain Injury. Surg Today 2005; 35:751-9. [PMID: 16133670 DOI: 10.1007/s00595-005-3034-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2004] [Accepted: 11/16/2004] [Indexed: 10/25/2022]
Abstract
PURPOSE To determine the optimal time to start nutritional support after traumatic brain injury (TBI). METHODS Rats were divided into six groups of seven. All but one of these groups were subjected to moderate closed head trauma under general anesthesia. Groups Ia and Ib were commenced on immunonutrition and standard enteral nutrition, respectively, 8 h later; groups IIa and IIb were commenced on immunonutrition and standard enteral nutrition, respectively, 72 h later; and group III was commenced on a parenteral saline infusion 8 h later. Group IV was a control group fed a laboratory diet and not subjected to trauma. The rats were killed 7 days later, and ileal segments were examined using light and electron microscopy. We used the deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) technique to detect intestinal mucosal apoptosis. RESULTS Group III had a lower body weight than the other groups (P < 0.005). The mean villous height was highest in groups Ia and IV and lowest in group III. The villi count was lower in groups Ib, IIa, IIb, and III than in group IV (P < 0.005). The apoptotic index counts were higher in groups IIa, IIb, and III than in group IV (P < 0.005). CONCLUSIONS The addition of enriching immunonutrients to early enteral feeding helps preserve an almost normal gut mucosa.
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Affiliation(s)
- Sevim Aydin
- Department of Histology, Karadeniz Technical University, Farabi Hospital, Anabilim Dali, 61080, Trabzon, Turkey
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Abstract
Recent studies have demonstrated that hypopituitarism, and in particular growth hormone (GH) deficiency, is common among survivors of traumatic brain injury (TBI) tested several months or years following head trauma. In addition, it has been shown that post-traumatic neuroendocrine abnormalities occur early and with high frequency. These findings may have significant implications for the recovery and rehabilitation of patients with TBI. Although data emerging after 2000 demonstrate the relevance of the problem, in general there is a lack of awareness in the medical community about the incidence and clinical repercussions of the pathology. Most, but not all, head trauma associated with hypopituitarism is the result of motor accidents. The subjects at risk are those who have suffered moderate-to severe head trauma although mild intensity trauma may precede hypopituitarism also. Particular attention should be paid to this problem in children and adolescents. Onset of pituitary deficits can evolve over years following injury. For the assessment of the GH-IGF axis in TBI patients, plasma IGF-I concentrations, plus dynamic GH testing is indicated. Some degree of hypopituitarism is found in 35-40% of TBI patients. Among multiple pituitary deficits, the most common ones were GHD and gonadotrophin deficiency. In most series 10-15% presented with severe GHD and 15% with partial GHD after stimulating GH secretion confirming that the most common isolated deficit is GHD. Psychometric evaluation together with neurocognitive testing shows variability of disability and the possibility that untreated TBI induced hypopituitarism contributes to the chronic neurobehavioral problems seen in many head-injured patients warrants consideration. Preliminary data, from small pilot, open-label studies show that subjects treated with GH experience significant improvements in concentration, memory, depression, anxiety and fatigue. In conclusion, pituitary failure can occur even in minor head injuries and is poorly recognized.
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Affiliation(s)
- V Popovic
- Neuroendocrine Unit, Institute of Endocrinology, University Clinical Center, Dr Subotic 13, 11000 Belgrade, Serbia.
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Grundy PL, Patel N, Harbuz MS, Lightman SL, Sharples PM. Adrenalectomy further suppresses the NT-3 mRNA response to traumatic brain injury but this effect is not reversed with corticosterone. ACTA ACUST UNITED AC 2004; 120:188-92. [PMID: 14741409 DOI: 10.1016/j.molbrainres.2003.09.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Fluid percussion injury (FPI) and in situ hybridisation were used to evaluate the expression of NT-3 mRNA in the hippocampus after traumatic brain injury (TBI) in adrenal-intact and adrenalectomised rats (with or without corticosterone replacement). FPI and adrenalectomy independently significantly reduced the expression of NT-3 mRNA in the dentate gyrus (DG) and CA2 region. The effects of adrenalectomy in the CA2 region were partially reversed with corticosterone. In adrenalectomised animals undergoing FPI, a further significant decrease in NT-3 mRNA was observed in the DG, but this was not reversed by corticosterone. Glucocorticoids may, therefore, play a role in the basal regulation of NT-3 in the hippocampus, but the role of glucocorticoids in the modulation of the NT-3 response to TBI is unclear.
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Affiliation(s)
- Paul L Grundy
- Department of Neurosurgery, Frenchay Hospital, Bristol, BS16 1LE, UK.
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Hang CH, Shi JX, Li JS, Wu W, Li WQ, Yin HX. Levels of vasoactive intestinal peptide, cholecystokinin and calcitonin gene-related peptide in plasma and jejunum of rats following traumatic brain injury and underlying significance in gastrointestinal dysfunction. World J Gastroenterol 2004; 10:875-80. [PMID: 15040036 PMCID: PMC4727008 DOI: 10.3748/wjg.v10.i6.875] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To study the alterations of brain-gut peptides following traumatic brain injury (TBI) and to explore the underlying significance of these peptides in the complicated gastrointestinal dysfunction.
METHODS: Rat models of focal traumatic brain injury were established by impact insult method, and divided into 6 groups (6 rats each group) including control group with sham operation and TBI groups at postinjury 3, 12, 24, 72 h, and d 7. Blood and proximal jejunum samples were taken at time point of each group and gross observations of gastrointestinal pathology were recorded simultaneously. The levels of vasoactive intestinal peptide (VIP) in plasma, calcitonin gene-related peptide (CGRP) and cholecystokinin (CCK) in both plasma and jejunum were measured by enzyme immunoassay (EIA). Radioimmunoassay (RIA) was used to determine the levels of VIP in jejunum.
RESULTS: Gastric distension, delayed gastric emptying and intestinal dilatation with a large amount of yellowish effusion and thin edematous wall were found in TBI rats through 12 h and 72 h, which peaked at postinjury 72 h. As compared with that of control group (247.8 ± 29.5 ng/L), plasma VIP levels were significantly decreased at postinjury 3, 12 and 24 h (106.7 ± 34.1 ng/L, 148.7 ± 22.8 ng/L, 132.8 ± 21.6 ng/L, respectively), but significantly increased at 72 h (405.0 ± 29.8 ng/L) and markedly declined on d 7 (130.7 ± 19.3 ng/L). However, Plasma levels CCK and CGRP were significantly increased through 3 h and 7 d following TBI (126-691% increases), with the peak at 72 h. Compared with control (VIP, 13.6 ± 1.4 ng /g; CGRP, 70.6 ± 17.7 ng/g); VIP and CGRP levels in jejunum were significantly increased at 3 h after TBI (VIP, 35.4 ± 5.0 ng/g; CGRP, 103.8 ± 22.1 ng/g), and declined gradually at 12 h and 24 h (VIP, 16.5 ± 1.8 ng/g, 5.5 ± 1.4 ng/g; CGRP, 34.9 ± 9.7 ng/g, 18.5 ± 7.7 ng/g), but were significantly increased again at 72 h (VIP, 48.7 ± 9.5 ng/g; CGRP, 142.1 ± 24.3 ng/g), then declined in various degrees on d 7 (VIP, 3.8 ± 1.1 ng/g; CGRP, 102.5 ± 18.1 ng/g). The CCK levels in jejunum were found to change in a similar trend as that in plasma with the concentrations of CCK significantly increased following TBI (99-517% increases) and peaked at 72 h.
CONCLUSION: Traumatic brain injury can lead to significant changes of brain-gut peptides in both plasma and small intestine, which may be involved in the pathogenesis of complicated gastrointestinal dysfunction.
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Affiliation(s)
- Chun-Hua Hang
- Department of Neurosurgery, Jinling Hospital, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, China.
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Hang CH, Shi JX, Li JS, Wu W, Yin HX. Alterations of intestinal mucosa structure and barrier function following traumatic brain injury in rats. World J Gastroenterol 2003; 9:2776-81. [PMID: 14669332 PMCID: PMC4612051 DOI: 10.3748/wjg.v9.i12.2776] [Citation(s) in RCA: 144] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Gastrointestinal dysfunction is a common complication in patients with traumatic brain injury (TBI). However, the effect of traumatic brain injury on intestinal mucosa has not been studied previously. The aim of the current study was to explore the alterations of intestinal mucosa morphology and barrier function, and to determine how rapidly the impairment of gut barrier function occurs and how long it persists following traumatic brain injury.
METHODS: Male Wistar rats were randomly divided into six groups (6 rats each group) including controls without brain injury and traumatic brain injury groups at hours 3, 12, 24, and 72, and on day 7. The intestinal mucosa structure was detected by histopathological examination and electron microscopy. Gut barrier dysfunction was evaluated by detecting serum endotoxin and intestinal permeability. The level of serum endotoxin and intestinal permeability was measured by using chromogenic limulus amebocyte lysate and lactulose/mannitol (L/M) ratio, respectively.
RESULTS: After traumatic brain injury, the histopathological alterations of gut mucosa occurred rapidly as early as 3 hours and progressed to a serious state, including shedding of epithelial cells, fracture of villi, focal ulcer, fusion of adjacent villi, dilation of central chyle duct, mucosal atrophy, and vascular dilation, congestion and edema in the villous interstitium and lamina propria. Apoptosis of epithelial cells, fracture and sparseness of microvilli, loss of tight junction between enterocytes, damage of mitochondria and endoplasm, were found by electron microscopy. The villous height, crypt depth and surface area in jejunum decreased progressively with the time of brain injury. As compared with that of control group (183.7 ± 41.8 EU/L), serum endotoxin level was significantly increased at 3, 12, and 24 hours following TBI (434.8 ± 54.9 EU/L, 324.2 ± 61.7 EU/L and 303.3 ± 60.2 EU/L, respectively), and peaked at 72 hours (560.5 ± 76.2 EU/L), then declined on day 7 (306.7 ± 62.4 EU/L, P < 0.01). Two peaks of serum endotoxin level were found at hours 3 and 72 following TBI. L/M ratio was also significantly higher in TBI groups than that in control group (control, 0.0172 ± 0.0009; 12 h, 0.0303 ± 0.0013; 24 h, 0.0354 ± 0.0025; 72 h, 0.0736 ± 0.0105; 7 d, 0.0588 ± 0.0083; P < 0.01).
CONCLUSION: Traumatic brain injury can induce significant damages of gut structure and impairment of barrier function which occur rapidly as early as 3 hours following brain injury and lasts for more than 7 days with marked mucosal atrophy.
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Affiliation(s)
- Chun-Hua Hang
- Medical College of Nanjing University, Nanjing 210002, Jiangsu Province, China.
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