title: Delayed inhibition of angiotensin II receptor type 1 reduces secondary brain damage and improves functional recovery after experimental brain trauma*.
abstract: OBJECTIVE
  To investigate the regulation of the cerebral renin-angiotensin system and the effect of angiotensin II receptor type 1 inhibition on secondary brain damage, cerebral inflammation, and neurologic outcome after head trauma.
  
  
  METHODS
  The expression of renin-angiotensin system components was determined at 15 mins, 3 hrs, 6 hrs, 12 hrs, and 24 hrs after controlled cortical impact in mice. Angiotensin II receptor type 1 was inhibited using candesartan (0.1, 0.5, 1 mg/kg) after trauma to determine its effect on secondary brain damage, brain edema formation, and inflammation. The window of opportunity was tested by delaying angiotensin II receptor type 1 inhibition for 30 mins, 1 hr, 2 hrs, and 4 hrs. The long-term effect was tested by single and daily repeated treatment with candesartan for 5 days after controlled cortical impact.
  
  
  METHODS
  University research laboratory.
  
  
  METHODS
  Male C57Bl/6N mice.
  
  
  METHODS
  Brain trauma by use of a controlled cortical impact device.
  
  
  RESULTS
  Expression of angiotensin II receptor type 1A decreased by 42% within 24 hrs after controlled cortical impact, whereas angiotensin II receptor type 1B expression increased to 220% between 6 and 12 hrs. Blockage of angiotensin II receptor type 1 with 0.1 mg/kg candesartan within 4 hrs of injury significantly reduced secondary brain damage (30 mins: 25 mm vs. vehicle: 41 mm) and improved neurologic function after 24 hrs but failed to reduce brain edema formation. Daily treatment with candesartan afforded sustained reduction of brain damage and improved neurologic function 5 days after traumatic brain injury compared with single and vehicle treatment. Inhibition of angiotensin II receptor type 1 significantly attenuated posttraumatic inflammation (interleukin-6: -56%; interleukin-1β: -42%; inducible nitric oxide synthase: -36%; tumor necrosis factor-α: -35%) and microglia activation (vehicle: 163 ± 25/mm vs. candesartan: 118 ± 13/mm). Higher dosages (0.5 and 1 mg/kg) resulted in prolonged reduction in blood pressure and failed to reduce brain lesion.
  
  
  CONCLUSIONS
  The results indicate that angiotensin II receptor type 1 plays a key role in the development of secondary brain damage after brain trauma. Inhibition of angiotensin II receptor type 1 with a delay of up to 4 hrs after traumatic brain injury effectively reduces lesion volume. This reduction makes angiotensin II receptor type 1 a promising therapeutic target for reducing cerebral inflammation and limiting secondary brain damage.
authors.affiliation: Department of Anesthesiology, Medical Center of Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Timaru-Kast
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wyschkon
authors.forename: Clara
authors.initials: C
authors.lastname: Luh
authors.forename: Eva-Verena
authors.initials: EV
authors.lastname: Schaible
authors.forename: Florian
authors.initials: F
authors.lastname: Lehmann
authors.forename: Philipp
authors.initials: P
authors.lastname: Merk
authors.forename: Christian
authors.initials: C
authors.lastname: Werner
authors.forename: Kristin
authors.initials: K
authors.lastname: Engelhard
authors.forename: Serge C
authors.initials: SC
authors.lastname: Thal
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001930:Brain Injuries / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020127:Recovery of Function / Q000187:drug effects; D012084:Renin-Angiotensin System
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers