HOMEPRODUCTSSERVICESCOMPANYCONTACTFAQResearchDictionaryPharmaMobileSign Up FREE or Login

Tissue protective effect of xanthine oxidase inhibitor, polymer conjugate of (styrene-maleic acid copolymer) and (4-amino-6-hydroxypyrazolo[3,4-d]pyrimidine), on hepatic ischemia-reperfusion injury.

Abstract
The detrimental role of superoxide anion (O(2)(-)) has been well documented in the pathogenesis of ischemia-reperfusion (I/R) injury. Our and other studies suggested that one critical source of O(2)(-) generation may be xanthine oxidase (XO). We thus hypothesized that I/R injury could be protected by inhibiting XO activity, which would reduce the amount of O(2)(-) and hence reduce pathogenic consequences. Among various XO inhibitors, we previously found 4-amino-6-hydroxypyrazolo[3,4-d]pyrimidine (AHPP) exhibited potent XO inhibitory activity. Here, we report that the covalent conjugate of AHPP with amphipathic styrene-maleic acid copolymer (SMA-AHPP) showed protective effect against I/R-induced injury in a rat hepatic I/R model. Liver ischemia was induced by occluding both the portal vein and the hepatic artery for 30 min, and followed by reperfusion. SMA-AHPP was administered via the tail vein two hours before ischemia was initiated. A remarkable increase of liver enzymes in plasma (aspartate aminotransferase, AST; alanine aminotransferase, ALT and lactate dehydrogenase, LDH) was detected three hours after reperfusion, whereas prior injection of SMA-AHPP greatly suppressed this increase of AST, ALT and LDH. Moreover, induction of inflammatory cytokines, i.e. tumor necrosis factor-alpha (TNF-alpha), interleukin-12 (IL-12) and monocyte chemotactic protein-1 (MCP-1) by I/R were significantly inhibited by SMA-AHPP treatment. Accordingly, cytotoxic effect or apoptosis in the liver caused by I/R was clearly reduced by SMA-AHPP pretreatment. Furthermore, thiobarbituric acid-reactive substance assay showed a significant decrease of lipid peroxidation in rat liver after the administration of SMA-AHPP, which is parallel with the decreased XO activity after SMA-AHPP treatment, indicating the involvement of reactive oxygen species generated by XO. In addition, SMA-AHPP was found to bind to albumin, thus to exhibit prolonged in vivo (plasma) half-life. These results suggest that SMA-AHPP exerted a potent cytoprotective effect against I/R injury in rat liver, by inhibiting XO activity and the subsequent generation of O(2)(-).
AuthorsJun Fang, Takahiro Seki, Haibo Qin, Gahininath Y Bharate, Arun K Iyer, Hiroshi Maeda
JournalExperimental biology and medicine (Maywood, N.J.) (Exp Biol Med (Maywood)) Vol. 235 Issue 4 Pg. 487-96 (Apr 2010) ISSN: 1535-3699 [Electronic] England
PMID20407081 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 4-amino-6-hydroxypyrazolo(3,4-d)pyrimidine
  • Albumins
  • Cytokines
  • Enzyme Inhibitors
  • Maleates
  • Polystyrenes
  • Thiobarbituric Acid Reactive Substances
  • Superoxides
  • styrene-maleic acid polymer
  • Heme Oxygenase-1
  • Xanthine Oxidase
  • Oxypurinol
Topics
  • Albumins (metabolism)
  • Animals
  • Apoptosis (drug effects)
  • Cytokines (blood)
  • Enzyme Inhibitors (chemistry, pharmacology)
  • Heme Oxygenase-1 (metabolism)
  • Liver (blood supply, drug effects, metabolism, pathology)
  • Male
  • Maleates (chemistry, pharmacology)
  • Molecular Weight
  • Oxypurinol (analogs & derivatives, chemistry, pharmacology)
  • Polystyrenes (chemistry, pharmacology)
  • Rats
  • Rats, Wistar
  • Reperfusion Injury (metabolism, pathology, prevention & control)
  • Superoxides (metabolism)
  • Thiobarbituric Acid Reactive Substances (metabolism)
  • Tissue Distribution
  • Xanthine Oxidase (antagonists & inhibitors, metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!


Choose Username:
Email:
Password:
Verify Password: