Bilirubin oxidation products (BOXes) and their role in cerebral vasospasm after subarachnoid hemorrhage

Joseph F. Clark, Frank R Sharp

Research output: Contribution to journalArticlepeer-review

89 Scopus citations


Many factors have been postulated to cause delayed subarachnoid hemorrhage (SAH)-induced vasospasm, including hemoglobin, nitric oxide, endothelin, and free radicals. We propose that free radicals (because of the high levels that are produced in the blood clots surrounding blood vessels after SAH) act on bilirubin, biliverdin, and possibly heme to produce BOXes (Bilirubin OXidized Products). Bilirubin oxidation products act on vascular smooth muscle cells to produce chronic vasoconstriction and vasospasm combined with a vasculopathy because of smooth muscle cell injury. This review summarizes recent evidence that BOXes play a role in SAH-induced vasospasm. The data supporting a role for BOXes includes (1) identification of molecules in cerebrospinal fluid (CSF) of patients with vasospasm after SAH that have structures consistent with BOXes; (2) BOXes are vasoactive in vitro and mimic the biochemical actions of CSF of patients with vasospasm; (3) BOXes are vasoactive in vivo, constricting rat cerebral vessels; and (4) there is a correlation between clinical occurrence of vasospasm and BOXes concentration in our preliminary study of patients with SAH. Since oxidation of bilirubin, biliverdin, and perhaps heme is proposed to produce BOXes that contribute to vasospasm, either blocking bilirubin formation, inactivating bilirubin or BOXes, or removing all of the blood clot before vasospasm are potential treatment targets.

Original languageEnglish (US)
Pages (from-to)1223-1233
Number of pages11
JournalJournal of Cerebral Blood Flow and Metabolism
Issue number10
StatePublished - Oct 18 2006


  • Bilirubin oxidation
  • Bilirubin Oxidation products
  • Hemorrhage
  • Stroke
  • Subarachnoid hemorrhage
  • Vasospasm

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)
  • Endocrinology, Diabetes and Metabolism


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