title: Chronotherapeutic effect of fisetin on expression of urea cycle enzymes and inflammatory markers in hyperammonaemic rats.
abstract: BACKGROUND
  Elevated blood ammonia leads to hyperammonaemia that affects vital central nervous system (CNS) functions. Fisetin, a naturally occurring flavonoid, exhibits therapeutic benefits, such as anti-cancer, anti-diabetic, anti-oxidant, anti-angiogenic, neuroprotective and neurotrophic effects.
  
  
  METHODS
  In this study, the chronotherapeutic effect of fisetin on ammonium chloride (AC)-induced hyperammonaemic rats was investigated, to ascertain the time point at which the maximum drug effect is achieved. The anti-hyperammonaemic potential of fisetin (50mg/kg b.w. oral) was analysed when administered to AC treated (100mg/kg b.w. i.p.) rats at 06:00, 12:00, 18:00 and 00:00h. Amelioration of pathophysiological conditions by fisetin at different time points was measured by analysing the levels of expression of liver urea cycle enzymes (carbamoyl phosphate synthetase-I (CPS-I), ornithine transcarbamoylase (OTC) and argininosuccinate synthetase (ASS)), nuclear transcription factor kappaB (NF-κB p65), brain glutamine synthetase (GS) and inducible nitric oxide synthase (iNOS) by Western blot analysis.
  
  
  RESULTS
  Fisetin increased the expression of CPS-I, OTC, ASS and GS and decreased iNOS and NF-κB p65 in hyperammonaemic rats. Fisetin administration at 00:00h showed more significant effects on the expression of liver and brain markers, compared with other time points.
  
  
  CONCLUSIONS
  Fisetin could exhibit anti-hyperammonaemic effect owing to its anti-oxidant and cytoprotective influences. The temporal variation in the effect of fisetin could be due to the (i) chronopharmacological, chronopharmacokinetic properties of fisetin and (ii) modulations in the endogenous circadian rhythms of urea cycle enzymes, brain markers, redox enzymes and renal clearance during hyperammonaemia by fisetin. However, future studies in these lines are necessitated.
authors.affiliation: Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Chidambaram, India. Electronic address: psub@rediffmail.com.
authors.forename: Perumal
authors.initials: P
authors.lastname: Subramanian
authors.affiliation: Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Chidambaram, India.
authors.forename: Murugesan
authors.initials: M
authors.lastname: Jayakumar
authors.affiliation: University of Malaya Centre for Proteomics Research (UMCPR), Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Jaime Jacqueline
authors.initials: JJ
authors.lastname: Jayapalan
authors.affiliation: University of Malaya Centre for Proteomics Research (UMCPR), Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Onn Haji
authors.initials: OH
authors.lastname: Hashim
mesh_terms: D000643:Ammonium Chloride / Q000633:toxicity; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D055870:Drug Chronotherapy; D005419:Flavonoids / Q000008:administration & dosage / Q000494:pharmacology*; D044948:Flavonols; D022124:Hyperammonemia / Q000188:drug therapy*; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D014508:Urea / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D005419:Flavonoids; D044948:Flavonols; D000643:Ammonium Chloride; D014508:Urea; C017875:fisetin
keywords: Chronotherapy; Circadian; Fisetin; Hyperammonaemia; Urea cycle