Bolus Administration of Polyamines Boosts Effects on Hepatic Ischemia-Reperfusion Injury and Regeneration in Rats

Abstract

Background:It was demonstrated that polyamines ameliorate ischemia-reperfusion injury (IRI) and promote regeneration in the liver. An optimal protocol of polyamine treatment remains unknown in the clinical setting. We examined 2 types of administration methods using rat models. Methods: Experiment 1: evaluation of pharmacokinetics of polyamines. Experiment 2: for 3 days preoperatively and 5 days postoperatively, polyamines were given to male Lewis rats in the following three groups: the control group, no polyamine administration; the chow group, 0.05% polyamines mixed in chow; the bolus group, polyamines (200 μmol/kg) given by gastric tube once a day. All rats received 70% hepatectomy after 40 min of warm IRI. Postoperatively, IRI and regeneration were evaluated with assessment of serum levels of hepatic enzymes, histology and immunohistochemistry of liver tissue, and measurement of remnant liver weight. Results: The blood concentrations of polyamines in the portal vein increased at 1 h of bolus administration, while they did not increase without the bolus. The bolus group was significantly associated with lower serum levels of aspartate/alanine aminotransferases (p < 0.05), decreased hepatocyte congestion, vacuolization and necrosis in histopathological scoring (p < 0.05), a lower number of TUNEL-positive hepatocytes (p < 0.05), higher remnant liver weight at 24, 48, and 168 h (p < 0.05), and a higher Ki-67 labeling index (24 h, p < 0.01) compared with the chow group. Conclusion: The bolus administration of polyamines was more effective in ameliorating IRI and promoting regeneration than chow administration. Perioperative bolus administration of polyamines might be an optimal treatment, when clinically applied.

Cross-species metabolomic analysis identifies uridine as a potent regeneration promoting factor

“…Among these, glutathione metabolism plays an important role in defensing against oxidant 33,34 , and was recently reported to be activated in liver regeneration 35 . In addition, polyamine metabolites (e.g., spermine and spermidine) are well-known pro-regenerative metabolites [36][37][38] . Taken together, these data imply a metabolic preference underlying high regenerative ability.…”

Activation of whole body by high levels of polyamine intake in rats

“…Recently, we found that perioperative oral polyamine administration attenuates liver ischemia-reperfusion injury and promotes liver regeneration (Doi et al 2019;Okumura et al 2016). In a liver ischemia-reperfusion injury, the number of PCNA (Proliferation cell nuclear antigen)-positive and Ki67-positive cells were increased in the polyamine group compared to the non-polyamine group.…”

Increased hepatic putrescine levels as a new potential factor related to the progression of metabolic dysfunction‐associated steatotic liver disease

“…For instance, previous studies have demonstrated that putrescine levels increase after partial hepatectomy, but quickly decrease with recovery, which could be associated with induction of hepatocyte proliferation and liver regeneration [26]. Moreover, spermidine and spermine have been shown to alleviate ischemia reperfusion injury in liver and correlated with reduction in the levels of AST, ALT, vacuolization, necrosis, and apoptosis after 6 h administration [27]. On the other hand, the abrogation of SSAT, the rate‐limiting enzyme in polyamine back conversion, has been described to reduce tissue damage in an acute liver injury model which seemed to be independent of polyamine levels [28].…”