title: Selective Brain-Targeted Antagonism of p38 MAPKα Reduces Hippocampal IL-1β Levels and Improves Morris Water Maze Performance in Aged Rats.
abstract: BACKGROUND
  P38 mitogen activated protein kinase (MAPK) α modulates microglia-mediated inflammatory responses and a number of neuronal physiological processes.
  
  
  OBJECTIVE
  To evaluate pre-clinically the pharmacological effects in the brain of p38 MAPKα inhibition with a brain-penetrant specific chemical antagonist.
  
  
  METHODS
  VX-745, a blood-brain barrier penetrant, highly selective p38 MAPKα inhibitor, and clinical stage investigational drug, was utilized. Initially, a pilot study in 26-month-old Tg2576 mice was conducted. Subsequently, a definitive dose-response study was conducted in aged (20-22 months) rats with identified cognitive deficits; n = 15 per group: vehicle, 0.5, 1.5, and 4.5 mg/kg VX-745 by oral gavage twice daily for 3 weeks. Assessments in aged rats included IL-1β, PSD-95, TNFα protein levels in hippocampus; and Morris water maze (MWM) test for cognitive performance.
  
  
  RESULTS
  Drug effect could not be assessed in Tg2576 mice, as little inflammation was evident. In cognitively-impaired aged rats, VX-745 led to significantly improved performance in the MWM and significant reduction in hippocampal IL-1β protein levels, though the effects were dissociated as the MWM effect was evident at a lower dose level than that required to lower IL-1β. Drug concentration-effect relationships and predicted human doses were determined.
  
  
  CONCLUSIONS
  Selective inhibition of p38 MAPKα with VX-745 in aged rats reduces hippocampal IL-1β levels and improves performance in the MWM. As the two effects occur at different dose levels, the behavioral effect appears to be via a mechanism that is independent of reducing cytokine production. The predicted human doses should minimize risks of systemic toxicity.
authors.forename: John J
authors.initials: JJ
authors.lastname: Alam
mesh_terms: D000375:Aging; D000818:Animals; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000097:blood / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D007859:Learning Disabilities / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D018782:Maze Learning / Q000187:drug effects*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011724:Pyridazines / Q000097:blood / Q000627:therapeutic use*; D011743:Pyrimidines / Q000097:blood / Q000627:therapeutic use*; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D018709:Statistics, Nonparametric; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D008565:Membrane Proteins; D011724:Pyridazines; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D051528:Guanylate Kinases; C464966:VX-745
keywords: Aged rats; Alzheimer’s disease; IL-1β; Tg2576 mouse; amyloid plaque; cognition; p38 MAPKα