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

(2016) Haas, J. de (Job)

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.

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