J. Huang et al., Dehydroascorbic acid, a blood-brain barrier transportable form of vitamin C, mediates potent cerebroprotection in experimental stroke, P NAS US, 98(20), 2001, pp. 11720-11724
Citations number
43
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Neuronal injury in ischemic stroke is partly mediated by cytotoxic reactive
oxygen species. Although the antioxidant ascorbic acid (AA) or vitamin C d
oes not penetrate the blood-brain barrier (BBB), its oxidized form, dehydro
ascorbic acid (DHA), enters the brain by means of facilitative transport. W
e hypothesized that i.v. DHA would improve outcome after stroke because of
its ability to cross the BBB and augment brain antioxidant levels. Reversib
le or permanent focal cerebral ischemia was created by intraluminal middle
cerebral artery occlusion in mice treated with vehicle, AA, or DHA (40, 250
, or 500 mg/kg), either before or after ischemia. Given before ischemia, DH
A caused dose-dependent increases in postreperfusion cerebral blood flow, w
ith reductions in neurological deficit and mortality. In reperfused cerebra
l ischemia, mean infarct volume was reduced from 53% and 59% in vehicle- an
d AA-treated animals, respectively, to 15% in 250 mg/kg DHA-treated animals
(P < 0.05). Similar significant reductions occurred in nonreperfused cereb
ral ischemia. Delayed postischemic DHA administration after 15 min or 3 h a
lso mediated improved outcomes. DNA (250 mg/kg or 500 mg/kg) administered a
t 3 h postischemia reduced infarct volume by 6- to 9-fold, to only 5% with
the highest DHA dose (P < 0.05). In contrast, AA had no effect on infarct v
olumes, mortality, or neurological deficits. No differences in the incidenc
e of intracerebral hemorrhage occurred. Unlike exogenous AA, DHA confers in
vivo, dose-dependent neuroprotection in reperfused and nonreperfused cereb
ral ischemia at clinically relevant times. As a naturally occurring interco
nvertible form of AA with BBB permeability, DHA represents a promising phar
macological therapy for stroke based on its effects in this model of cerebr
al ischemia.