title: Protection against focal ischemic injury to the brain by trans-sodium crocetinate. Laboratory investigation.
abstract: OBJECTIVE
  Ischemic injury is a potential complication in a variety of surgical procedures and is a particular impediment to the success of surgeries involving highly vulnerable neural tissue. One approach to limiting this form of injury is to enhance metabolic supply to the affected tissue. Trans-sodium crocetinate (TSC) is a carotenoid compound that has been shown to increase tissue oxygenation by facilitating the diffusivity of small molecules, such as oxygen and glucose. The present study examined the ability of TSC to modify oxygenation in ischemic neural tissue and tested the potential neuroprotective effects of TSC in permanent and temporary models of focal cerebral ischemia.
  
  
  METHODS
  Adult male rats (330–370 g) were subjected to either permanent or temporary focal ischemia by simultaneous occlusion of both common carotid arteries and the left middle cerebral artery (3-vessel occlusion [3-VO]). Using the permanent ischemia paradigm, TSC was administered intravenously beginning 10 minutes after the onset of ischemia at 1 of 8 dosages, ranging from 0.023 to 4.580 mg/kg. Cerebral infarct volume was measured 24 hours after the onset of ischemia. The effect of TSC on infarct volume was also tested after temporary (2-hour) ischemia using a dosage of 0.092 mg/kg. In other animals undergoing temporary ischemia, tissue oxygenation was monitored in the ischemic penumbra using a Licox probe.
  
  
  RESULTS
  Administration of TSC reduced infarct volume in a dose-dependent manner in the permanent ischemia model, achieving statistical significance at dosages ranging from 0.046 to 0.229 mg/kg. The most effective dosage of TSC in the permanent ischemia experiment (0.092 mg/kg) was further tested using a temporary (2-hour) ischemia paradigm. Infarct volume was reduced significantly by TSC in this ischemia-reperfusion model as well. Recordings of oxygen levels in the ischemic penumbra of the temporary ischemia model showed that TSC increased tissue oxygenation during vascular occlusion, but reduced the oxygen overshoot (hyperoxygenation) that occurs upon reperfusion.
  
  
  CONCLUSIONS
  The novel carotenoid compound TSC exerts a neuroprotective influence against permanent and temporary ischemic injury when administered soon after the onset of ischemia. The protective mechanism of TSC remains to be confirmed; however, the permissive effect of TSC on the diffusivity of small molecules is a plausible mechanism based on the observed increase in tissue oxygenation in the ischemic penumbra. This represents a form of protection based on “metabolic reflow” that can occur under conditions of partial vascular perfusion. It is particularly noteworthy that TSC could conceivably limit the progression of a wide variety of cellular injury mechanisms by blunting the ischemic challenge to the brain.
authors: Department of Neuroscience, University of Virginia, Charlottesville, Virginia 22908, USA. ksl3h@virginia.edu
authors: Hiroaki
authors: H
authors: Manabe
authors: David O
authors: DO
authors: Okonkwo
authors: John L
authors: JL
authors: Gainer
authors: Ryon H
authors: RH
authors: Clarke
authors: Kevin S
authors: KS
authors: Lee
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects; D002545:Brain Ischemia / Q000473:pathology / Q000517:prevention & control*; D002338:Carotenoids; D017536:Carotid Artery, Common / Q000473:pathology; D002544:Cerebral Infarction / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000502:physiology; D002546:Ischemic Attack, Transient / Q000473:pathology; D008026:Ligation; D008297:Male; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014801:Vitamin A / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: C487773:trans-sodium crocetinate; D014801:Vitamin A; D002338:Carotenoids