Novel mitochondrial transition pore inhibitor N-methyl-4-isoleucine cyclosporin is a new therapeutic option in acute pancreatitis

Tóth, Emese [Tóth, Emese (Pancreas experime...), szerző] I. sz. Belgyógyászati Klinika (SZTE / ÁOK); Maléth, József [Maléth, József (Gasztroenterológia), szerző] I. sz. Belgyógyászati Klinika (SZTE / ÁOK); MTA-SZTE Lendület Epitél Sejt Szignalizáció és ... (SZTE / ÁOK / I.BelK); Závogyán, Noémi; Fanczal, Júlia [Fanczal, Júlia (pancreatitis (ala...), szerző] I. sz. Belgyógyászati Klinika (SZTE / ÁOK); MTA-SZTE Lendület Epitél Sejt Szignalizáció és ... (SZTE / ÁOK / I.BelK); Grassalkovich, Anna; Erdős, Réka; Pallagi, Petra [Pallagi, Petra (Gasztroenterológia), szerző] I. sz. Belgyógyászati Klinika (SZTE / ÁOK); Horváth, Gergő; Tretter, László [Tretter, László (Biokémia), szerző] Orvosi Biokémiai Intézet (SE / AOK / I); Bálint, Emese Réka; Rakonczay, Zoltán; Venglovecz, Viktória [Venglovecz, Viktória (Pankreász), szerző] Farmakológiai és Farmakoterápiai Intézet (SZTE / ÁOK); Hegyi, Péter [Hegyi, Péter (Gasztroenterológia), szerző] I.sz. Belgyógyászati Klinika (PTE / ÁOK); MTA-SZTE Lendület Gasztroenterológiai Multidisz... (SZTE / ÁOK / I.BelK); Transzlációs Medicina Intézet (PTE / ÁOK); Transzlációs medicina kutatócsoport (PTE / SZKK)

Angol nyelvű Tudományos Szakcikk (Folyóiratcikk)
Megjelent: JOURNAL OF PHYSIOLOGY-LONDON 0022-3751 1469-7793 597 (24) pp. 5879-5898 2019
  • SJR Scopus - Sports Science: D1
Azonosítók
•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. All rights reserved.
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2020-02-17 10:10