title: Pomalidomide mitigates neuronal loss, neuroinflammation, and behavioral impairments induced by traumatic brain injury in rat.
abstract: Traumatic brain injury (TBI) is a global health concern that typically causes emotional disturbances and cognitive dysfunction. Secondary pathologies following TBI may be associated with chronic neurodegenerative disorders and an enhanced likelihood of developing dementia-like disease in later life. There are currently no approved drugs for mitigating the acute or chronic effects of TBI.
  
  
  
  The effects of the drug pomalidomide (Pom), an FDA-approved immunomodulatory agent, were evaluated in a rat model of moderate to severe TBI induced by controlled cortical impact. Post-TBI intravenous administration of Pom (0.5 mg/kg at 5 or 7 h and 0.1 mg/kg at 5 h) was evaluated on functional and histological measures that included motor function, fine more coordination, somatosensory function, lesion volume, cortical neurodegeneration, neuronal apoptosis, and the induction of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6).
  
  
  
  Pom 0.5 mg/kg administration at 5 h, but not at 7 h post-TBI, significantly mitigated the TBI-induced injury volume and functional impairments, neurodegeneration, neuronal apoptosis, and cytokine mRNA and protein induction. To evaluate underlying mechanisms, the actions of Pom on neuronal survival, microglial activation, and the induction of TNF-α were assessed in mixed cortical cultures following a glutamate challenge. Pom dose-dependently ameliorated glutamate-mediated cytotoxic effects on cell viability and reduced microglial cell activation, significantly attenuating the induction of TNF-α.
  
  
  
  Post-injury treatment with a single Pom dose within 5 h significantly reduced functional impairments in a well-characterized animal model of TBI. Pom decreased the injury lesion volume, augmented neuronal survival, and provided anti-inflammatory properties. These findings strongly support the further evaluation and optimization of Pom for potential use in clinical TBI.
authors.affiliation: Graduate Institute of Medical Science, College of Medicine, Taipei Medical University, 250 Wu-Hsing St., Taipei, 110, Taiwan.
authors.forename: Jin-Ya
authors.initials: JY
authors.lastname: Wang
authors.affiliation: Graduate Institute of Medical Science, College of Medicine, Taipei Medical University, 250 Wu-Hsing St., Taipei, 110, Taiwan.|Department of Nursing, Hsin Sheng Junior College of Medical Care and Management, Taoyuan, Taiwan.
authors.forename: Ya-Ni
authors.initials: YN
authors.lastname: Huang
authors.affiliation: Department of General Surgery, Chi Mei Medical Center, Tainan and Liouying, Taiwan.
authors.forename: Chong-Chi
authors.initials: CC
authors.lastname: Chiu
authors.affiliation: Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, USA.
authors.forename: David
authors.initials: D
authors.lastname: Tweedie
authors.affiliation: Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, USA.
authors.forename: Weiming
authors.initials: W
authors.lastname: Luo
authors.affiliation: Department of Anatomy and Anthropology, Sackler School of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Chaim G
authors.initials: CG
authors.lastname: Pick
authors.affiliation: Graduate Program on Neuroregeneration, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Szu-Yi
authors.initials: SY
authors.lastname: Chou
authors.affiliation: Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Hoffer
authors.affiliation: Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, USA. greign@mail.NIH.gov.
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
authors.affiliation: Graduate Institute of Medical Science, College of Medicine, Taipei Medical University, 250 Wu-Hsing St., Taipei, 110, Taiwan. jywang2010@tmu.edu.tw.|Department of Physiology, College of Medicine, Taipei Medical University, 250 Wu-Hsing St., Taipei, 110, Taiwan. jywang2010@tmu.edu.tw.
authors.forename: Jia-Yi
authors.initials: JY
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000070642:Brain Injuries, Traumatic / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy* / Q000209:etiology; D007839:Functional Laterality / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007155:Immunologic Factors / Q000627:therapeutic use*; D008297:Male; D000068079:Motor Disorders / Q000188:drug therapy* / Q000209:etiology; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000209:etiology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011596:Psychomotor Disorders / Q000188:drug therapy* / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020886:Somatosensory Disorders / Q000188:drug therapy* / Q000209:etiology; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D007155:Immunologic Factors; D013792:Thalidomide; C467566:pomalidomide; D010751:Phosphopyruvate Hydratase
keywords: Controlled cortical impact; Glutamate excitotoxicity; Interleukin-1β; Interleukin-6; Neuroinflammation; Neuronal apoptosis; Pomalidomide; Thalidomide; Traumatic brain injury; Tumor necrosis factor-α