We previously reported that
uridine blocked
glucose deprivation-induced death of immunostimulated astrocytes by preserving
ATP levels.
Uridine phosphorylase (UPase), an
enzyme catalyzing the reversible phosphorylation of
uridine, was involved in this effect. Here, we tried to expand our previous findings by investigating the
uridine effect on the brain and neurons using in vivo and in vitro ischemic injury models. Orally administrated
uridine (50-200 mg/kg) reduced
middle cerebral artery occlusion (1.5 h)/reperfusion (22 h)-induced
infarct in mouse brain. Additionally, in the rat brain subjected to the same ischemic condition, UPase
mRNA and
protein levels were up-regulated. Next, we employed
glucose deprivation-induced
hypoglycemia in mixed cortical cultures of neurons and astrocytes as an in vitro model. Cells were deprived of
glucose and, two hours later, supplemented with 20 mM
glucose. Under this condition, a significant
ATP loss followed by death was observed in neurons but not in astrocytes, which were blocked by treatment with
uridine in a concentration-dependent manner. Inhibition of cellular uptake of
uridine by S-(4-nitrobenzyl)-6-thioinosine blocked the
uridine effect. Similar to our in vivo data, UPase expression was up-regulated by
glucose deprivation in
mRNA as well as
protein levels. Additionally, 5-(phenylthio)acyclouridine, a specific inhibitor of UPase, prevented the
uridine effect. Finally, the
uridine effect was shown only in the presence of astrocytes. Taken together, the present study provides the first evidence that
uridine protects neurons against ischemic insult-induced neuronal death, possibly through the action of UPase.