Hepatocellular uptake of cyclodextrin‐complexed curcumin during liver preservation: A feasibility study

Abstract

The increasing demand for donor organs and the decreasing organ quality is prompting research toward new methods to reduce ischemia reperfusion injury (IRI). Several strategies have been proposed to protect preserved organs from this injury. Before curcumin/dextrin complex (CDC), a potent antioxidant and anti-inflammatory agent, can be used clinically we need to better understand the intracellular uptake under hypothermic conditions on a rat model of liver donation after circulatory death (DCD) and brain death (DBD). To be able to use the fluorescence of CDC for quantification the stability of CDC in different preservation solutions at 4°C or 37°C was investigated. Livers from Wistar rats were procured after being flushed-out through the portal vein using CDC-enriched preservation solutions and stored at 4°C for variable periods. The CDC signal was stable in different preservation solutions over a period of 4 h and allowed the rapid and lasting uptake of curcumin into cells. After 4 h of preservation, CDC was no longer visible microscopically, and HPLC analysis showed very low to non-detectable tissue levels of CDC, proving metabolization during preservation. However, the distribution of CDC was not affected by warm ischemia damage (p = 0.278) nor by flushing the livers before or after 4 h of cold storage and without a warm preflush. Finally, curcumin reduced oxidative stress, lowered histological injury and did not change gene expression after WI/cold storage. Therefore, the use of CDC flush solution for the initial organ flush can offer a promising approach to the enhancement of liver preservation and the maintenance of its quality.

Combating Ischemia-Reperfusion Injury with Micronutrients and Natural Compounds during Solid Organ Transplantation: Data of Clinical Trials and Lessons of Preclinical Findings

“…Interestingly, the anti-inflammatory effects have also been observed for remote lung injury [ 112 ]. Moreover, the addition of curcumin into a preservation solution has been shown to protect against oxidative stress and histological injury after cold [ 116 ] as well as warm [ 116 ] storage. Finally, the protective effects of curcumin culminated into the increased post-transplantation survival of treated animals.…”

“…[88] intracardial injection [89] improved energy metabolism increase of aerobic energy production [85] preservation/delay of aerobic efficiency [85] preservation of mitochondrial function [90] improved organ function [87] improved myocardial function [86] decreased oxidative injury [86] reduced cardiac stunning time [88] reduced area of infarction risk [89] anti-inflammatory effects [96] inhibition of NFκB [96] inhibition of NMDA [96] induction of Nrf2 pathway [96] anti-apoptotic effects [96] inhibition of caspase 3 [96] induction of NO/cGMP/PKG pathway [96] antifibrotic effects [96] activation of APPL [96] inhibition of Akt [96] Liver mouse [108] rat [109][110][111][112][113][114]116] in vitro [114,115] i.p. [108] p.o.…”

“…[109,110] i.v. [111,113] preservation solution [116] prevention of liver injury [108][109][110][111] attenuated liver enzymes AST, ALT [112,113] restoration of ATP content [110] protection against injury during warm und cold storage [116] increased survival [116] anti-inflammatory effects reduced expression of proinflammatory cytokines [114] reduced expression of adhesion molecules [113,115] anti-inflammatory priming of Kupffer cells [108] inhibition of NFκB [114] lower pulmonary levels of TNFα and MMP-9 activity [112] antioxidative effects activation of antioxidant enzymes [112] upregulation of HO-1 [111] Hsp70 expression [111] Heart rat [128][129][130][131]135,280] in vitro [129,134,137,138] mouse [132,133] intracardial injection [128] perfusion solution [129,280] p.o. [130,132,133,135] i.p.…”

Therapeutic potential of curcumin in ARDS and COVID‐19

“…Because of their hydrophilic outer surface and lipophilic cavity, CDs can solubilize hydrophobic drugs. To address the solubility concern, a novel curcumin formulation (cyclodextrin‐complexed curcumin (CDC)) was developed by complexing the compound with hydroxypropyl‐γ‐cyclodextrin (CD) 17 , 23 Specifically, curcumin was prepared at a concentration of 15 g/L. The solution was agitated, and after the complete dissolution of curcumin, the pH was adjusted to 6.0 with a mixture of hydrochloric acid and citric acid.…”

“…The recovered CDC solution contained 12 g/L curcumin and 93 g/L cyclodextrins in 20 mM sodium citrate and 100 mM NaCl solution. 23 This dramatically enhances water solubility and stability, facilitating direct pulmonary delivery. 24 Fluorescence microscopic examination revealed an association of curcumin with cells throughout the lung.…”