title: Attenuation of traumatic brain injury-induced cognitive impairment in mice by targeting increased cytokine levels with a small molecule experimental therapeutic.
abstract: BACKGROUND
  Evidence from clinical studies and preclinical animal models suggests that proinflammatory cytokine overproduction is a potential driving force for pathology progression in traumatic brain injury (TBI). This raises the possibility that selective targeting of the overactive cytokine response, a component of the neuroinflammation that contributes to neuronal dysfunction, may be a useful therapeutic approach. MW151 is a CNS-penetrant, small molecule experimental therapeutic that selectively restores injury- or disease-induced overproduction of proinflammatory cytokines towards homeostasis. We previously reported that MW151 administered post-injury (p.i.) is efficacious in a closed head injury (CHI) model of diffuse TBI in mice. Here we test dose dependence of MW151 to suppress the target mechanism (proinflammatory cytokine up-regulation), and explore the therapeutic window for MW151 efficacy.
  
  
  METHODS
  We examined suppression of the acute cytokine surge when MW151 was administered at different times post-injury and the dose-dependence of cytokine suppression. We also tested a more prolonged treatment with MW151 over the first 7 days post-injury and measured the effects on cognitive impairment and glial activation.
  
  
  RESULTS
  MW151 administered up to 6 h post-injury suppressed the acute cytokine surge, in a dose-dependent manner. Administration of MW151 over the first 7 days post-injury rescues the CHI-induced cognitive impairment and reduces glial activation in the focus area of the CHI.
  
  
  CONCLUSIONS
  Our results identify a clinically relevant time window post-CHI during which MW151 effectively restores cytokine production back towards normal, with a resultant attenuation of downstream cognitive impairment.
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, 800 S Limestone Street, Lexington, KY, USA. adam.bachstetter@uky.edu.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Bachstetter
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, 800 S Limestone Street, Lexington, KY, USA. scott.webster@uky.edu.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Webster
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, 800 S Limestone Street, Lexington, KY, USA. dsgoul2@uky.edu.
authors.forename: Danielle S
authors.initials: DS
authors.lastname: Goulding
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, 800 S Limestone Street, Lexington, KY, USA. jonathan.morton@uky.edu.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Morton
authors.affiliation: Department of Pharmacology, Northwestern University, 303 E Chicago Avenue, Chicago, IL, USA. d.m.watterson@gmail.com.
authors.forename: D Martin
authors.initials: DM
authors.lastname: Watterson
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, 800 S Limestone Street, Lexington, KY, USA. linda.vaneldik@uky.edu.|Department of Anatomy and Neurobiology, University of Kentucky, 800 Rose Street, Lexington, KY, USA. linda.vaneldik@uky.edu.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Van Eldik
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001930:Brain Injuries / Q000150:complications*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology*; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D011724:Pyridazines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D013997:Time Factors
chemical_list: C575875:2-(4-(4-methyl-6-phenylpyridazin-3-yl)piperazin-1-yl)pyrimidine; C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D011724:Pyridazines; D011743:Pyrimidines