Antioxidant CR-6 protects against reperfusion injury after a transient episode of focal brain ischemia in rats.
Oxidative and nitrosative stress are targets for intervention after ischemia/reperfusion. The aim of this study was to explore the effect of CR-6, a vitamin-E analogue that is antioxidant and scavenger of nitrogen-reactive species. Sprague-Dawley rats had the middle cerebral artery (MCA) occluded either for 90 mins or permanently. Cortical perfusion was continuously monitored by laser-Doppler flowmetry. CR-6 (100 mg/kg) was administered orally either at 2 and 8 h after MCA occlusion, or at 2 h only. Infarct volume, neurological deficit, and signs of reperfusion injury were evaluated. CR-6 was detected in plasma and brain by HPLC. CR-6 reduced glutathione consumption in the ischemic brain and superoxide generation in the isolated MCA. CR-6 decreased infarct volume and attenuated the neurological deficit at 1 and 7 days after ischemia/reperfusion, but not after permanent ischemia. Immediately after reperfusion, cortical blood flow values returned to their baseline (+/-20%) in several animals, whereas others showed hyper-perfusion (>20% of baseline). Reactive hyperemia was associated with adverse events such as increased cortical BBB leakage, edema, protein nitrotyrosination, COX-2 expression, and neutrophil accumulation; and with a poorer outcome, and CR-6 attenuated these effects. In conclusion, oral CR-6 administration after transient ischemia protects the brain from reperfusion injury.
Pérez-Asensio
Fernando J
FJ
Department of Brain Ischemia and Neurodegeneration, Institut d'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones Científicas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona E-08036, Spain.
de la Rosa
Xavier
X
Jiménez-Altayó
Francesc
F
Gorina
Roser
R
Martínez
Emili
E
Messeguer
Angel
A
Vila
Elisabet
E
Chamorro
Angel
A
Planas
Anna M
AM
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D001929:Brain Edema / Q000473:pathology / Q000517:prevention & control; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D002544:Cerebral Infarction / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D006940:Hyperemia / Q000097:blood; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D007249:Inflammation / Q000473:pathology; D007962:Leukocytes / Q000473:pathology; D008297:Male; D018696:Neuroprotective Agents; D020556:Neutrophil Infiltration; D018384:Oxidative Stress / Q000187:drug effects; D011597:Psychomotor Performance / Q000502:physiology; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D026361:Reactive Nitrogen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*
D000975:Antioxidants; D001578:Benzopyrans; C120400:CR 6; D018696:Neuroprotective Agents; D026361:Reactive Nitrogen Species; D012313:RNA; D051546:Cyclooxygenase 2