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

Tóth, Emese and Maléth, József and Závogyán, Noémi and Fanczal, Júlia and Grassakovich, Anna and Erdős, Réka and Pallagi, Petra and Horváth, Gergő and Tretter, László and Bálint, Emese Réka and Rakonczay, Zoltán and Venglovecz, Viktória and Hegyi, Péter (2019) Novel mitochondrial transition pore inhibitor N‐methyl‐4‐isoleucine cyclosporin is a new therapeutic option in acute pancreatitis. JOURNAL OF PHYSIOLOGY - LONDON, 597 (24). pp. 5879-5898. ISSN 0022-3751

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Abstract

Bile acids, ethanol and fatty acids affect pancreatic ductal fluid and bicarbonate secretion via mitochondrial damage, ATP depletion and calcium overload. •Pancreatitis-inducing factors open the membrane transition pore (mPTP) channel via cyclophilin D activation in acinar cells, causing calcium overload and cell death; genetic or pharmacological inhibition of mPTP improves the outcome of acute pancreatitis in animal models. •Here we show that genetic and pharmacological inhibition of mPTP protects mitochondrial homeostasis and cell function evoked by pancreatitis-inducing factors in pancreatic ductal cells. •The results also show that the novel cyclosporin A derivative NIM811 protects mitochondrial function in acinar and ductal cells, and it preserves bicarbonate transport mechanisms in pancreatic ductal cells. •We found that NIM811 is highly effective in different experimental pancreatitis models and has no side-effects. NIM811 is a highly suitable compound to be tested in clinical trials.

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