title: Uridine prevents the glucose deprivation-induced death of immunostimulated astrocytes via the action of uridine phosphorylase.
abstract: We previously reported that in immunostimulated astrocytes, glucose deprivation induced cell death via the loss of ATP, reduced glutathione, and mitochondrial transmembrane potential. The cytotoxicity was due to reactive nitrogen and oxygen species and blocked by adenosine, a purine nucleoside, via the preservation of cellular ATP. Here, we investigated whether uridine, a pyrimidine nucleoside, could prevent the glucose deprivation-induced cytotoxicity in LPS+IFN-gamma-treated (immunostimulated) astrocytes. Glucose deprivation induced the death of immunostimulated cells, which was significantly reduced by uridine. Glucose deprivation rapidly decreased cellular ATP levels in immunostimulated astrocytes, which was also reversed by uridine. The inhibition of cellular uptake of uridine by S-(4-nitrobenzyl)-6-thioinosine attenuated the protective effect of uridine. mRNA and protein expression for uridine phosphorylase, an enzyme catalyzing reversible phosphorolysis of uridine, were observed in rat brain as well as primary astrocytes. 5-(Phenylthio)acyclouridine (PTAU), a specific inhibitor of uridine phosphorylase, inhibited the protective effect of uridine. Additionally, the loss of mitochondrial transmembrane potential and reduced glutathione by glucose deprivation in immunostimulated cells was attenuated by uridine, which was also reversed by PTAU. These results provide the first evidence that uridine protects immunostimulated astrocytes against the glucose deprivation-induced death by preserving intracellular ATP through the action of uridine phosphorylase.
authors.affiliation: Department of Pharmacology, College of Pharmacy, Seoul National University, Shillim-Dong, Kwanak-Gu, Seoul, Republic of Korea.
authors.forename: Ji Woong
authors.initials: JW
authors.lastname: Choi
authors.forename: Byoung-Kwon
authors.initials: BK
authors.lastname: Yoo
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Shin
authors.forename: Mi-Kyoung
authors.initials: MK
authors.lastname: Ryu
authors.forename: Jong Hoon
authors.initials: JH
authors.lastname: Ryu
authors.forename: Mahmoud H
authors.initials: MH
authors.lastname: el Kouni
authors.forename: Jae-Chul
authors.initials: JC
authors.lastname: Lee
authors.forename: Won-Ki
authors.initials: WK
authors.lastname: Kim
authors.forename: Kwang Ho
authors.initials: KH
authors.lastname: Ko
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D016923:Cell Death / Q000502:physiology*; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007114:Immunization; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008564:Membrane Potentials; D018696:Neuroprotective Agents / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014529:Uridine / Q000378:metabolism*; D014543:Uridine Phosphorylase / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D007371:Interferon-gamma; D000255:Adenosine Triphosphate; D014543:Uridine Phosphorylase; D005978:Glutathione; D005947:Glucose; D014529:Uridine