Dehydroascorbic acid, a blood–brain barrier transportable form of vitamin C, mediates potent cerebroprotection in experimental stroke

Abstract

Neuronal injury in ischemic stroke is partly mediated by cytotoxic reactive oxygen species. Although the antioxidant ascorbic acid (AA) or vitamin C does not penetrate the blood-brain barrier (BBB), its oxidized form, dehydroascorbic acid (DHA), enters the brain by means of facilitative transport. We hypothesized that i.v. DHA would improve outcome after stroke because of its ability to cross the BBB and augment brain antioxidant levels. Reversible 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 mg͞kg), either before or after ischemia. Given before ischemia, DHA caused dose-dependent increases in postreperfusion cerebral blood flow, with reductions in neurological deficit and mortality. In reperfused cerebral ischemia, mean infarct volume was reduced from 53% and 59% in vehicle-and AA-treated animals, respectively, to 15% in 250 mg͞kg DHAtreated animals (P < 0.05). Similar significant reductions occurred in nonreperfused cerebral ischemia. Delayed postischemic DHA administration after 15 min or 3 h also mediated improved outcomes. DHA (250 mg͞kg or 500 mg͞kg) administered at 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 volumes, mortality, or neurological deficits. No differences in the incidence of intracerebral hemorrhage occurred. Unlike exogenous AA, DHA confers in vivo, dose-dependent neuroprotection in reperfused and nonreperfused cerebral ischemia at clinically relevant times. As a naturally occurring interconvertible form of AA with BBB permeability, DHA represents a promising pharmacological therapy for stroke based on its effects in this model of cerebral ischemia.

Nifedipine treatment reduces brain damage after transient focal ischemia, possibly through its antioxidative effects

“…[2][3][4] We have also demonstrated the accumulation of lipid peroxidation products and the decrease in antioxidative enzymes in the ischemic hemispheres in our model at 2 days after MCAO and reperfusion. Previous studies have already reported the direct neuroprotective effects of CCBs during the early phase of ischemia reperfusion.…”

“…1 Oxidative stress has an important role in the pathogenesis of ischemic brain damage. [2][3][4] During ischemia, a robust influx of calcium (Ca 2+ ) activates glutamate receptors that induce the generation of reactive oxygen species from mitochondria 5 and reactive nitrogen species, 6 leading to lipid peroxidation. 7 L-type Ca 2+ channels and N-methyl-D-aspartate receptors have a crucial role in the entry of Ca 2+ into neurons.…”

Hyperpolarized 13 C dehydroascorbate as an endogenous redox sensor for in vivo metabolic imaging

“…Total brain Vitamin C levels are under strong homeostatic regulation, with extracellular Vitamin C concentrations mediated in part by heteroexchange with glutamate (46). High levels of brain Vitamin C are neuroprotective, and may be enhanced by administration of DHA, which readily crosses the blood-brain barrier (47 In each case the final concentration of DHA was 2.5 mM while the NaBH 3 CN concentration range was 5-100 mM, resulting in a measured pH of 4.5-5.5.…”

Noninvasive Assessment of the Brain Redox Status after Transient Middle Cerebral Artery Occlusion Using Overhauser-Enhanced Magnetic Resonance Imaging

“…As the levels of these antioxidants were decreased by the ischemia-reperfusion insult, their ability to defend the cells from oxidative stress was impaired. To counteract the decrease in antioxidants, transient MCAO mice can be treated with dehydroascorbic acid, which is transported to the blood-brain barrier and retained in the brain as ascorbic acid (Agus et al, 1997;Huang et al, 2001). Huang et al showed that the administration of dehydroascorbic acid significantly improves the cerebral blood flow and functional outcome, and significantly decreases the volume of infarcted brain tissue after ischemia-reperfusion.…”