title: Dipyrone inhibits neuronal cell death and diminishes hypoxic/ischemic brain injury.
abstract: BACKGROUND
  Dipyrone is an analgesic and antipyretic drug usually prescribed for patients with inflammatory conditions. We recently identified dipyrone as an antiapoptotic agent by screening a library of 1040 compounds for their ability to inhibit cytochrome c release from isolated mitochondria.
  
  
  OBJECTIVE
  We investigated the potential neuroprotective properties of dipyrone in cerebral ischemia.
  
  
  METHODS
  We evaluated the protective effects of dipyrone in experimental models of neuronal hypoxia/ischemia, including an oxygen/glucose deprivation model in primary cerebrocortical neurons and a focal cerebral ischemia model in mice.
  
  
  RESULTS
  Dipyrone reduced hypoxia/ischemia injury in both cellular and animal models. Dipyrone inhibited the release of cytochrome c and other mitochondrial apoptogenic factors from mitochondria into the cytoplasm, and attenuated subsequent caspase-9 and caspase-3 activation both in vitro and in vivo. Moreover, dipyrone prevented ischemia-induced changes in Bcl-2 and tBid, and ameliorated oxygen/glucose deprivation-mediated loss of mitochondrial membrane potential. Dipyrone also inhibited ischemia-induced reactive microgliosis. In the cellular models evaluated, dipyrone did not inhibit oxygen/glucose deprivation-induced cyclooxygenase-2 activation.
  
  
  CONCLUSIONS
  Dipyrone is remarkably neuroprotective in cerebral ischemia, and its cyclooxygenase-independent protective properties are, at least in part, due to the inhibition of mitochondrial cell death cascades.
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Sergei V
authors.initials: SV
authors.lastname: Baranov
authors.forename: Shan
authors.initials: S
authors.lastname: Zhu
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Huang
authors.forename: Wendy
authors.initials: W
authors.lastname: Fellows-Mayle
authors.forename: Jiying
authors.initials: J
authors.lastname: Jiang
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Day
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Kristal
authors.forename: Robert M
authors.initials: RM
authors.lastname: Friedlander
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004177:Dipyrone / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy*; D007150:Immunohistochemistry; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018696:Neuroprotective Agents; D004177:Dipyrone; D051546:Cyclooxygenase 2