title: Caffeine protects against experimental acute pancreatitis by inhibition of inositol 1,4,5-trisphosphate receptor-mediated Ca2+ release.
abstract: Caffeine reduces toxic Ca2+signals in pancreatic acinar cells via inhibition of inositol 1,4,5-trisphosphate receptor (IP3R)-mediated signalling, but effects of other xanthines have not been evaluated, nor effects of xanthines on experimental acute pancreatitis (AP). We have determined effects of caffeine and its xanthine metabolites on pancreatic acinar IP3R-mediated Ca2+signalling and experimental AP.
  
  
  
  Isolated pancreatic acinar cells were exposed to secretagogues, uncaged IP3or toxins that induce AP and effects of xanthines, non-xanthine phosphodiesterase (PDE) inhibitors and cyclic adenosine monophosphate and cyclic guanosine monophosphate (cAMP/cGMP) determined. The intracellular cytosolic calcium concentration ([Ca2+]C), mitochondrial depolarisation and necrosis were assessed by confocal microscopy. Effects of xanthines were evaluated in caerulein-induced AP (CER-AP), taurolithocholic acid 3-sulfate-induced AP (TLCS-AP) or palmitoleic acid plus ethanol-induced AP (fatty acid ethyl ester AP (FAEE-AP)). Serum xanthines were measured by liquid chromatography-mass spectrometry.
  
  
  
  Caffeine, dimethylxanthines and non-xanthine PDE inhibitors blocked IP3-mediated Ca2+oscillations, while monomethylxanthines had little effect. Caffeine and dimethylxanthines inhibited uncaged IP3-induced Ca2+rises, toxin-induced Ca2+release, mitochondrial depolarisation and necrotic cell death pathway activation; cAMP/cGMP did not inhibit toxin-induced Ca2+rises. Caffeine significantly ameliorated CER-AP with most effect at 25 mg/kg (seven injections hourly); paraxanthine or theophylline did not. Caffeine at 25 mg/kg significantly ameliorated TLCS-AP and FAEE-AP. Mean total serum levels of dimethylxanthines and trimethylxanthines peaked at >2 mM with 25 mg/kg caffeine but at <100 µM with 25 mg/kg paraxanthine or theophylline.
  
  
  
  Caffeine and its dimethylxanthine metabolites reduced pathological IP3R-mediated pancreatic acinar Ca2+signals but only caffeine ameliorated experimental AP. Caffeine is a suitable starting point for medicinal chemistry.
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of Liverpool, Liverpool, UK.|Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.|Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cane
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of Liverpool, Liverpool, UK.|Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Mukherjee
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of Liverpool, Liverpool, UK.|Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Szatmary
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of Liverpool, Liverpool, UK.|Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhang
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of Liverpool, Liverpool, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Elliott
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of Liverpool, Liverpool, UK.|Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Ouyang
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of Liverpool, Liverpool, UK.|Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Chvanov
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of Liverpool, Liverpool, UK.
authors.forename: Diane
authors.initials: D
authors.lastname: Latawiec
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of Liverpool, Liverpool, UK.|Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wen
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Booth
authors.affiliation: Immuno-Inflammation Therapeutic Area Unit, GlaxoSmithKline, Stevenage, UK.
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Haynes
authors.affiliation: Cardiff School of Biosciences, Cardiff University, Cardiff, UK.
authors.forename: Ole H
authors.initials: OH
authors.lastname: Petersen
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Alexei V
authors.initials: AV
authors.lastname: Tepikin
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of Liverpool, Liverpool, UK.|Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: David N
authors.initials: DN
authors.lastname: Criddle
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of Liverpool, Liverpool, UK.
authors.forename: Robert
authors.identifier: 0000-0001-6600-562X
authors.initials: R
authors.lastname: Sutton
mesh_terms: D061354:Acinar Cells / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002110:Caffeine / Q000494:pharmacology* / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002108:Ceruletide; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D000431:Ethanol; D005229:Fatty Acids, Monounsaturated; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009336:Necrosis / Q000000981:diagnostic imaging; D010179:Pancreas / Q000473:pathology*; D010195:Pancreatitis / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D013658:Taurolithocholic Acid / Q000031:analogs & derivatives; D014970:Xanthines / Q000097:blood / Q000494:pharmacology
chemical_list: D005229:Fatty Acids, Monounsaturated; D053496:Inositol 1,4,5-Trisphosphate Receptors; D010726:Phosphodiesterase Inhibitors; D014970:Xanthines; C066776:taurolithocholic acid 3-sulfate; C008757:palmitoleic acid; D002110:Caffeine; D000431:Ethanol; D013658:Taurolithocholic Acid; D015544:Inositol 1,4,5-Trisphosphate; D002108:Ceruletide; D000242:Cyclic AMP; D006152:Cyclic GMP; D002118:Calcium
keywords: ACUTE PANCREATITIS; CALCIUM; DRUG DEVELOPMENT