title: Flavonoids and phenylethanoid glycosides from Lippia nodiflora as promising antihyperuricemic agents and elucidation of their mechanism of action.
abstract: BACKGROUND
  Lippia nodiflora has been traditionally used in the Ayurvedic, Unani, and Sidha systems, as well as Traditional Chinese Medicine (TCM) for the treatment of knee joint pain, lithiasis, diuresis, urinary disorder and swelling.
  
  
  OBJECTIVE
  The present study aims to investigate the antihyperuricemic effect of the L. nodiflora methanol extract, fractions, and chemical constituents and their mechanism of action in the rat model.
  
  
  METHODS
  The mechanisms were investigated by performing xanthine oxidase inhibitory, uricosuric, and liver xanthine oxidase/xanthine dehydrogenase (XOD/XDH) inhibitory studies in potassium oxonate- and hypoxanthine-induced hyperuricemic rats. The plant safety profile was determined using acute toxicity study. The molecular docking of the active compound to the xanthine oxidase was simulated using computer aided molecular modeling analysis.
  
  
  RESULTS
  Oral administration of methanol extract showed a dose-dependent reduction effect on the serum uric acid level of hyperuricemic rats. F3 was the most potent fraction in lowering the serum uric acid level of hyperuricemic rats. Bioactivity-guided purification of F3 afforded two phenylethanoid glycosides, arenarioside (1) and verbascoside (2) and three flavonoids, 6-hydroxyluteolin (3), 6-hydroxyluteolin-7-O-glycoside (4), and nodifloretin (5). The highest serum uric acid reduction effect was exhibited by 3 (66.94%) in hyperuricemic rats, followed by 5 (55.97%), 4 (49.16%), 2 (29.03%), and 1 (22.08%) at 0.2 mmol/kg. Dose-response investigation on 3 at doses of 0.05, 0.1, and 0.3 mmol/kg produced a significant dose-dependent reduction on the serum uric acid level of hyperuricemic rats. Repeated administration of F3 or 3 to the hyperuricemic rats for 10 continuous days resulted in a significant and progressive serum uric acid lowering effect in hyperuricemic rats. In contrast, methanol extract and F3 did not reduce serum uric acid level of normoruricemic rats. In addition, F4 significantly increased the uric acid excretion of hyperuricemic rats at 200mg/kg. No toxic effect was observed in rats administered with 5000 mg/kg of methanol extract or F3.
  
  
  CONCLUSIONS
  The potential application of L. nodiflora against hyperuricemia in the animal in accordance with its traditional uses has been demonstrated in the present study for the first time. The antihyperuricemic effect possessed by L. nodiflora was contributed mainly by liver XOD/XDH inhibitory activities and partially by uricosuric effect. Flavonoids mainly accountable for the uric acid lowering effect of L. nodiflora through the inhibition of XOD/XDH activities.
authors.affiliation: Discipline of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, University of Science Malaysia (Universiti Sains Malaysia), 11800 Minden, Penang, Malaysia.
authors.forename: Lee-Chuen
authors.initials: LC
authors.lastname: Cheng
authors.affiliation: Discipline of Pharmacology, School of Pharmaceutical Sciences, University of Science Malaysia (Universiti Sains Malaysia), 11800 Minden, Penang, Malaysia.
authors.forename: Vikneswaran
authors.initials: V
authors.lastname: Murugaiyah
authors.affiliation: Discipline of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, University of Science Malaysia (Universiti Sains Malaysia), 11800 Minden, Penang, Malaysia. Electronic address: kitlamc@gmail.com.
authors.forename: Kit-Lam
authors.initials: KL
authors.lastname: Chan
mesh_terms: D000818:Animals; D005419:Flavonoids / Q000494:pharmacology / Q000627:therapeutic use*; D006027:Glycosides / Q000494:pharmacology / Q000627:therapeutic use*; D006074:Gout Suppressants / Q000494:pharmacology / Q000627:therapeutic use*; D033461:Hyperuricemia / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D032411:Lippia; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D014527:Uric Acid / Q000097:blood; D014969:Xanthine Oxidase / Q000378:metabolism
chemical_list: D005419:Flavonoids; D006027:Glycosides; D006074:Gout Suppressants; D010936:Plant Extracts; D014527:Uric Acid; D014969:Xanthine Oxidase
keywords: Antihyperuricemic; Hypoxanthine-induced hyperuricemic rat; Lippia nodiflora; Liver xanthine oxidase and xanthine dehydrogenase; Serum uric acid; Uric acid excretion