Abstract
We previously demonstrated that the blockade of mGluR5 by 2-methyl-6(phenylethynyl)pyridine (MPEP) reduces both cold and warm ischemia/reperfusion injury. Here we evaluated whether MPEP reduces the hepatic preservation injury in rat livers from cardiac-death-donors (DCDs). Livers from DCD rats were isolated after an in situ warm ischemia (30 min) and preserved for 22 h at 4 °C with UW solution. Next, 10 mg/Kg MPEP or vehicle were administered 30 min before the portal clamping and added to the UW solution (3 µM). LDH released during washout was quantified. Liver samples were collected for iNOS, eNOS, NO, TNF-α, ICAM-1, caspase-3 and caspase-9 protein expression and nuclear factor-erythroid-2-related factor-2 (Nrf2) gene analysis. Lower LDH levels were detected in control grafts versus DCD groups. An increase in eNOS and NO content occurred after MPEP treatment; iNOS and TNF-α content was unchanged. ICAM-1 expression was reduced in the MPEP-treated livers as well as the levels of caspase-3 and caspase-9. Nrf2, oxidative stress-sensitive gene, was recovered to control value by MPEP. These results suggest that MPEP can be used to reclaim DCD livers subjected to an additional period of cold ischemia during hypothermic storage. MPEP protects against apoptosis and increased eNOS, whose overexpression has been previously demonstrated to be protective in hepatic ischemia/reperfusion damage.
Highlights
Metabotropic glutamate 5 receptor is a Group I mGlu subfamily of receptors coupled to the inositol trisphosphate/diacylglycerol pathway
Since during organ preservation by cold storage, eNOS contributes to increased graft viability [13], we evaluated the effect of MPEP on tissue eNOS content
Lower ICAM-1 levels, comparable with those found in the control group, were found in donors after circulatory death (DCD) livers preserved in presence of MPEP as compared with vehicle-treated group (Figure 3)
Summary
Metabotropic glutamate (mGlu) 5 receptor is a Group I mGlu subfamily of receptors coupled to the inositol trisphosphate/diacylglycerol pathway. We showed that the mGlu receptor has a permissive role in the onset of ischemic injury performed at 37 ◦ C (warm ischemia) in rat and mice hepatocytes; hepatocytes isolated from livers of mGlu receptor knock-out mice are protected against warm ischemic injury [3,4]. The necessity of increasing the quality of organ preservation has made it necessary to consider the use of pharmacological additives to reduce the vulnerability of DCD grafts [11]. Strategies to increase the number of functional donor organs involve pharmacological interventions in DCD procurement techniques that contribute to improved outcomes in DCD transplants [12]. Based on the above reports, we designed a study to test whether the use of MPEP, an mGluR5 allosteric inhibitor, reduces the hepatic preservation injury, increasing the utilization of grafts obtained from DCDs
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