•Bile acids, ethanol and fatty acids deteriorate pancreatic ductal fluid and bicarbonate
secretion via mitochondrial damage, ATP depletion and calcium overload. •It is known
that pancreatitis inducing factors open the membrane transition pore (mPTP) channel
via cyclophilin D activation in acinar cells causing calcium overload and cell death
and genetic or pharmacological inhibition of mPTP improves the outcome of acute pancreatitis
in animal models. •In our study we show that genetic and pharmacological inhibition
of mPTP protects mitochondrial homeostasis and cell function evoked by pancreatitis-inducing
factors in pancreatic ductal cells. •Our results also reveal that the novel Cyclosporin
A derivative NIM811 protects mitochondrial function in acinar and ductal cells, moreover
it preserves bicarbonate transport mechanisms in pancreatic ductal cells. •We found
that NIM811 is highly effective in different experimental pancreatitis models and
that NIM811 has no side-effects. NIM811 is a highly suitable compound to be tested
in clinical trials .Background and aims Mitochondrial dysfunction plays a crucial
role in the development of acute pancreatitis (AP); however, no compound is currently
available with clinically acceptable effectiveness and safety. In this study, we investigated
the effects of a novel mitochondrial transition pore inhibitor, N-methyl-4-isoleucine
cyclosporin (NIM811), in AP. Methods Pancreatic ductal and acinar cells were isolated
by enzymatic digestion from Bl/6 mice. In vitro measurements were performed by confocal
microscopy and microfluorometry. Preventive effects of pharmacological (cylosporin
A (2 µM), NIM811 (2 µM)) or genetic (Ppif-/- /Cyp D KO) inhibition of the mitochondrial
transition pore (mPTP) during the administration of either bile acids (BA) or ethanol
+ fatty acids (EtOH+FA) were examined. Toxicity of mPTP inhibition was investigated
by detecting apoptosis and necrosis. In vivo effects of the most promising compound,
NIM811 (5 or 10 mg/kg per os), were checked in three different AP models induced by
either caerulein (10 × 50 µg/kg), ethanol+ fatty acid (1.75 g/kg ethanol and 750 mg/kg
palmitic acid) or 4% taurocholic acid (2 ml/kg). Results Both genetic and pharmacological
inhibition of Cyp D significantly prevented the toxic effects of BA and EtOH+FA by
restoring mitochondrial membrane potential (Δψ) and preventing the loss of mitochondrial
mass. In vivo experiments revealed that per os administration of NIM811 has a protective
effect in AP by reducing oedema, necrosis, leukocyte infiltration and serum amylase
level in AP models. Administration of NIM811 had no toxic effects. Conclusion The
novel mitochondrial transition pore inhibitor NIM811 seems to be an exceptionally
good candidate compound for clinical trials in AP. This article is protected by copyright.
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