title: Transiently lowering tumor necrosis factor-α synthesis ameliorates neuronal cell loss and cognitive impairments induced by minimal traumatic brain injury in mice.
abstract: BACKGROUND
  The treatment of traumatic brain injury (TBI) represents an unmet medical need, as no effective pharmacological treatment currently exists. The development of such a treatment requires a fundamental understanding of the pathophysiological mechanisms that underpin the sequelae resulting from TBI, particularly the ensuing neuronal cell death and cognitive impairments. Tumor necrosis factor-alpha (TNF-α) is a cytokine that is a master regulator of systemic and neuroinflammatory processes. TNF-α levels are reported to become rapidly elevated post TBI and, potentially, can lead to secondary neuronal damage.
  
  
  METHODS
  To elucidate the role of TNF-α in TBI, particularly as a drug target, the present study evaluated (i) time-dependent TNF-α levels and (ii) markers of apoptosis and gliosis within the brain and related these to behavioral measures of 'well being' and cognition in a mouse closed head 50 g weight drop mild TBI (mTBI) model in the presence and absence of post-treatment with an experimental TNF-α synthesis inhibitor, 3,6'-dithiothalidomide.
  
  
  RESULTS
  mTBI elevated brain TNF-α levels, which peaked at 12 h post injury and returned to baseline by 18 h. This was accompanied by a neuronal loss and an increase in astrocyte number (evaluated by neuronal nuclei (NeuN) and glial fibrillary acidic protein (GFAP) immunostaining), as well as an elevation in the apoptotic death marker BH3-interacting domain death agonist (BID) at 72 h. Selective impairments in measures of cognition, evaluated by novel object recognition and passive avoidance paradigms - without changes in well being, were evident at 7 days after injury. A single systemic treatment with the TNF-α synthesis inhibitor 3,6'-dithiothalidomide 1 h post injury prevented the mTBI-induced TNF-α elevation and fully ameliorated the neuronal loss (NeuN), elevations in astrocyte number (GFAP) and BID, and cognitive impairments. Cognitive impairments evident at 7 days after injury were prevented by treatment as late as 12 h post mTBI but were not reversed when treatment was delayed until 18 h.
  
  
  CONCLUSIONS
  These results implicate that TNF-α in mTBI induced secondary brain damage and indicate that pharmacologically limiting the generation of TNF-α post mTBI may mitigate such damage, defining a time-dependent window of up to 12 h to achieve this reversal.
authors: Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. renanaba@post.tau.ac.il.
authors: Renana
authors: R
authors: Baratz
authors: Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, BRC Room 05C220, 251 Bayview Blvd., Baltimore, MD, 21224, USA. tweedieda@grc.nia.nih.gov.
authors: David
authors: D
authors: Tweedie
authors: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan. jywang2010@tmu.edu.tw.
authors: Jia-Yi
authors: JY
authors: Wang
authors: Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Rubovitc@post.tau.ac.il.
authors: Vardit
authors: V
authors: Rubovitch
authors: Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, BRC Room 05C220, 251 Bayview Blvd., Baltimore, MD, 21224, USA. luowe@mail.nih.gov.
authors: Weiming
authors: W
authors: Luo
authors: Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH, USA. bjh82@case.edu.
authors: Barry J
authors: BJ
authors: Hoffer
authors: Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, BRC Room 05C220, 251 Bayview Blvd., Baltimore, MD, 21224, USA. greign@grc.nia.nih.gov.
authors: Nigel H
authors: NH
authors: Greig
authors: Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. pickc@post.tau.ac.il.
authors: Chaim G
authors: CG
authors: Pick
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000473:pathology*; D001930:Brain Injuries / Q000150:complications*; D003072:Cognition Disorders / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D009474:Neurons / Q000201:enzymology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects; D013792:Thalidomide / Q000031:analogs & derivatives / Q000737:chemistry / Q000627:therapeutic use; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C562075:3,6'-dithiothalidomide; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; D010751:Phosphopyruvate Hydratase