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PHOSPHOETANOLAMINE REDUCES HEPATIC ISCHEMIC INJURY BY A MECHANISM RELATED TO DECREASING SUCCINATE ACCUMULATION
Marcel C C. Machado
*, Marcia K. Koike, Denise F. Barbeiro, guilherme Rossini, Hermes Barbeiro, Francisco G. Soriano
Universidade de Sao Paulo, Sao Paulo, Brazil
Background Several previous studies showed that accumulation of the citric acid cycle intermediate succinate is presented in ischemic tissues and responsible for mitochondrial ROS production during reperfusion increasing tissue damage (1). Ischemic succinate accumulation during ischemia arises from reversal of succinate dehydrogenase driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle. Phosphoethanolamine (pETN) a biosynthetic precursor of phosphatidylethanolamine has been found to inhibit the succinate dehydrogenase may be a useful drug to decrease the hepatic Ischemic reperfusion injury. The aim of this study was evaluated effect of pETN in hepatic ischemic injury.
Method Rats were subjected to partial liver ischemia for 45 min and divided into 2 groups: Saline (n=8) and pETN (n=7). In pETN group, pETN (3mg/kg) was infused just before hepatic ischemia. The proportional amount of saline was infused in saline group. Succinate levels in the ischemic liver lobes were accessed, plasma levels of aspartate transferase (AST) and alanine transferase (ALT) were determined.
Results It was observed a significant reduction in succinate accumulation in ischemic liver from the pETN group (fig 1) together with a reduction in plasma levels of AST and ALT (fig 2) in comparison with Saline group.
Discussion Previous studies showed that there is a selective accumulation of succinate in ischemic tissues through a mechanism related to reversal of succinate dehydrogenase. The accumulation of succinate is reoxidized by succinate dehydrogenase with a great ROS generation by reversal electron transport at mitochondrial complex 1. In the present study we showed that pETN due to its inhibition effect on succinate dehydrogenase decreases the production of succinate in the ischemic liver and may be a suitable treatment for hepatic ischemic injury.
ConclusionsThis preliminary study demonstrates that the pETN, previous used even clinically to treat neoplasia (2), can be a valuable drug to reduces ischemia reperfusion injury not only in livers but also in many other organs or tissues.
References
1-Chouchani ET, Pell VR, Gaude E, et als. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature. 2014 Nov 20;515(7527):431-435. doi: 10.1038/nature13909. Epub 2014 Nov 5. PMID: 25383517; PMCID: PMC4255242.
2-Ferreira AK, Santana-Lemos BA, Rego EM, Synthetic phosphoethanolamine has in vitro and in vivo anti-leukemia effects. Br J Cancer. 2013; 109:2819– 28. [PubMed: 24201752] 15. Ferreira AKMR, Pereira A, M
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