Significant Improvement in Rat Kidney Cold Storage Using UW Organ Preservation Solution Supplemented With the Immediate-Acting PrC-210 Free Radical Scavenger

Abstract

Background. Ischemia-reperfusion injury, including injury from warm- and cold-ischemia (CI) organ storage, remains a significant problem for all solid organ transplants. Suppressing CI damage would reduce delayed graft function and increase the donor organ pool size. PrC-210 has demonstrated superior prevention of damage in several preclinical studies as an immediate-acting free-radical scavenger. Here, we describe its profound efficacy in suppressing CI injury in a rat kidney model. Methods. Kidneys in 300 gm Sprague-Dawley rats were perfused in situ with UW solution with or without added PrC-210 and then stored at 4°C in the same solution for 0 to 48 hours. When procured, kidney-activated caspase-3 level (a marker of cell death) was measured, and direct histological analysis of kidneys was performed to assess PrC-210 protective efficacy. In vitro analyses of PrC-210-conferred protection to isolated rat kidneys or naked DNA were also performed. Results. A single 15 seconds in situ perfusion of kidneys with 20 mmol/L PrC-210 in UW solution resulted in significant reductions in (1) 30-hour CI–induced kidney-activated caspase level (P < 0.0001); activated caspase was reduced to levels not significantly different than control activated caspase levels seen in unperturbed kidneys, (2) 30-hour CI–induced renal Tubular Injury Scores (P = 0.0004) where brush border and tubular necrosis were markedly reduced, (3) PrC-210 conferred 100% protection against ·OH damage to naked DNA and isolated kidney mitochondria while current UW solution antioxidants were without protective effect. Conclusions. A single PrC-210-UW solution perfusion of rat kidneys upon removal from the rat profoundly reduced caspase and renal tubular injury in kidneys exposed to 30 hours of CI organ storage. These findings support further development of the PrC-210 molecule to suppress or to prevent ischemia-reperfusion injury in organ transplant and other ischemia-reperfusion injury settings.

Significantly Improved Cold Preservation of Rat Hind Limb Vascularized Composite Allografts Using the New PrC-210 Free Radical Scavenger

“…Poyton [7] and Castello [8] attribute this organ CI damage to NO and ROS generated during the hypoxia of cold storage. The ROS-scavenging agent, PrC-210, has previously been shown to reduce both of these insults [20] and is therefore expected to confer a substantial improvement in the VCA transplant process.…”

“…An important advantage of PrC-210 is its "immediate action" as an ROS scavenger [20]. Its capacity for immediate action is attributed to PrC-210's small size (MW: 148) which allows simple transmembrane diffusion, while (+) charges function to localize it around (−) charged nucleic acids and proteins in both mitochondria and nuclei.…”

Systems for Genetic Assessment of the Impact of Environmental Factors

“…The direct mechanism of action is determined by the direct interaction of endogenous or exogenous factors with the DNA molecule, which leads to the breakdown of chemical bonds at the DNA level and initiates changes in its spatial structure [44,45]. The mechanism of mediated action by exogenous and endogenous factors is realized through their metabolism and activation of intermediate products, whose interaction with DNA underlies its damage [46,47]. While exogenous and endogenous factors have a great potential for modifying genetic information, the relative contribution of internal and external factors to the incidence of cancer remains uncertain [6].…”

The Effect of Antioxidant Added to Preservation Solution on the Protection of Kidneys before Transplantation

“…Verhoven et al [ 47 ] investigated the efficacy of PrC-210 in suppressing cold-ischemia injury in the Sprague-Dawley rats model. The authors measured kidney-activated caspase-3 level (a marker of cell death) and performed histological analysis.…”