Caffeine protects against experimental acute pancreatitis by inhibition of inositol 1,4,5-trisphosphate receptor-mediated Ca²⁺release

Abstract

ObjectiveCaffeine 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.DesignIsolated pancreatic acinar cells were exposed to secretagogues, uncaged IP3 or 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.ResultsCaffeine, 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.ConclusionsCaffeine 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.

Calcium signalling in the acinar environment of the exocrine pancreas: physiology and pathophysiology

“…; Huang et al . ). Because it has been established that fatty acids and ethanol can react together inside cells to produce FAEEs (Criddle et al .…”

New insights into the pathways initiating and driving pancreatitis

“…Two recent reports [43 ■■ ,44] demonstrate approaches to inhibit the pathologic SOCE channel activation and thus attenuate experimental pancreatitis. One study [43 ■■ ] showed that two Orai1in-hibitors prevented the increase in [Ca2+]c and necrosis in mouse and human acinar cells caused by agents that prevent refilling of the ER Ca2+ stores.…”

“…Furthermore, the Orai1 inhibitors attenuated acute pancreatitis responses in three dissimilar in-vivo models when given 1 h after the induction of pancreatitis, a clinically relevant design. Another study [44] used caffeine, a known inhibitor of IP3 receptor-mediated Ca2+ release from ER [45], to prevent sustained rises in [Ca2+]c and necrosis. Systemic administration of caffeine ameliorated pancreatitis responses in three experimental acute pancreatitis models.…”

Blood group B is associated with azathioprine-induced acute pancreatitis in patients with IBD

“…Based on these findings, the pathogenesis of thiopurine-induced acute pancreatitis seems to involve a combination of inherited risk factors, putative drug-allergic effects, the underlying IBD entity and patient-specific lifestyle factors. Newly detected possible protective factors against acute pancreatitis, as caffeine consumption5 or simvastatin,6 or the disease modifying effect of magnesium supplementation on the onset and course of acute experimental pancreatitis7 have not been taken in mind in this and previous AIAP studies. Actually, future research should focus on the question whether patients with IBD at high risk for AIAP (such as smokers with Crohn's disease) could benefit from predictive genetic testing—or at least from simple point-of-care blood group testing.…”