Protective Effects of Pharmacological TPRM2 Inhibition on Ischemia-reperfusion Injury of the liver

Haas, J. de (Job) (2016) Protective Effects of Pharmacological TPRM2 Inhibition on Ischemia-reperfusion Injury of the liver. thesis, Medicine.

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Abstract

IBsachckemgrioa-urnepde rfusion injury (IRI) of the liver is a common clinical problem after liver surgery and transplantation and new therapies are required to prevent it. Calcium overload in hepatocytes plays a central role in the pathogenesis of IRI, but the nature of the Ca+ channels responsible for this is unknown. Accumulating evidence shows that the Transient Receptor Potential Melastatin 2 (TRPM2) channel, which is activated in oxidative stress, could play a major role in Ca2+ overload. This study aims to investigate whether pharmacological inhibition of TRPM2 could reduce IRI of the liver in rats and mice. TMweoth doidffse rent types of experiments were conducted. In the first experiment, rats were subjected to 45 minutes of liver ischemia and 1 hour reperfusion. Each animal randomly received one of the TRPM2 inhibitors - chlorpromazine (n = 3), N-(p-amylcinnamoyl)anthranilic acid (ACA) (n = 3) or curcumin (n = 4). The control groups only received the vehicles (n = 3) prior to ischemia. Bile flow recovery during reperfusion was used to assess final liver damage. In the second experiment, mice were subjected to 45 minutes of liver ischemia and 24 hours of reperfusion. Each mouse randomly received either TRPM2 inhibitor curcumin (n = 8) or its vehicle (n = 7) prior to ischemia and at the start of reperfusion. TRPM2-KO mice were used as positive control group (n = 4). ALT and AST levels and liver histology after reperfusion were used to assess final liver damage. IRne tshuel tesx periments using rats, no significant difference in bile flow recovery was found between ACA and its vehicle, and between curcumin and its vehicle. Rats treated with chlorpromazine showed significantly less bile flow recovery compared to the vehicle treated group. In the experiments using mice, ischemia increased AST and ALT enzyme levels compared to sham-operated controls. No significant differences in ALT and AST levels were found between mice treated with curcumin and mice treated with its vehicle only. Interestingly, enzyme levels in TRPM2-KO mice were not significantly lower compared to levels in WT mice. Comparing percentages of necrosis, similar results were found between these groups. TChoenscel udsaitoan d o not show a reduction in liver IRI through pharmacological TRPM2 inhibition. Further research on the role of TRPM2 channels in liver IRI is needed.

Item Type:	Thesis (Thesis)
Supervisor name:	Nieuwenhuis, MD and Department of Surgery, Isala Zwolle The Netherlands
Supervisor name:	Rychkov, Professor G. PhD and Nutrition and Metabolism, South Australia Health and Medical and Adelaide, Australia and Barritt, Professor G. PhD and Department of Medical Biochemistry, Flinders University
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 10:40
Last Modified:	25 Jun 2020 10:40
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/217

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