Effect of poloxamer 407 administration on the serum lipids profile, anxiety level and protease activity in the heart and liver of mice

Abstract

Chronic administration of the poloxamer 407 (P-407), a block copolymer, to elevate serum lipids in mice is a well-established mouse model of hyperlipidemia and atherosclerosis. We tested the hypothesis that the activity of several types of proteases in heart and liver tissue is changed in the early stages of atherosclerosis development. Additionally, we evaluated whether increased serum lipids would induce anxiety in mice, as determined by using a ‘plus-maze’ test. The mice were administered P-407 by intraperitoneal injection twice a week for one month. P-407 administration to mice resulted in a marked increase in total serum cholesterol, atherogenic non-HDL-cholesterol, and especially in total triglycerides, and it also increased anxiety. Morphological changes observed in P-407-treated mice included contractile type changes in cardiomyocytes and foamy macrophages in liver. A significant increase of cysteine proteases cathepsin B and cathepsin L (at 24 h) and aspartate protease cathepsin D (at both 24 h and 5 days) was determined in heart tissue following P-407 administration. However, no changes were noted in heart matrix metalloproteinase activity. The activity of cysteine and aspartate proteases was significantly increased in liver at both 24 hours and 5 days after P-407 administration. In conclusion, administration of P-407 to mice for one month resulted in increased anxiety, and more importantly, there was an increase in the activity of heart and liver proteases secondary to sustained dyslipidemia. It is suggested that heart and liver cysteine and aspartate proteases may represent potential therapeutic targets in the early stages of atherosclerosis.

Hepatoprotective Effect of Camel Milk on Poloxamer 407 Induced Hyperlipidaemic Wistar Rats

“…This implies that the liver is a direct target for P407 as reported by Cogger et al, [ 32 ], whose findings showed that P407 has a marked effect on the ultrastructure of the liver sinusoidal endothelial cells (LSECs). Necrosis observed in liver tissues also agrees with the findings of Korolenko et al, [ 7 , 9 ]. The liver of atorvastatin treated groups showed moderate infiltration and necrosis.…”

“…The advantage with the P407 model is the production of hyperlipidaemia of the hereditary type [ 7 ]. Recent reports have shown the ability of P407 induced hyperlipidaemia to produce early and late stages of atherosclerosis [ 7 - 9 ] and alterations of liver transaminases and plasma proteins in rodents [ 7 - 11 ]. Consumption of synthetic hypolipidaemic drugs have been reported to cause hyperuricemia, diarrhea, nausea, myositis, gastric irritation, flushing, dry skin and abnormal liver function [ 12 ].…”

Hyperlipidemia control using the innovative association of lupin proteins and chitosan and α-cyclodextrin dietary fibers: food supplement formulation, molecular docking study, and in vivo evaluation

“…In this in vivo study, P-407, a non-ionic amphiphilic copolymer, was employed successfully for rapid induction of an acute hyperlipidemia model in rats as well documented in the literature [27,[40][41][42]. Based on the previous outcomes of Pan et al, a single injection of a high dose of P-407 can induce hyperlipidemia, showing lipid peak values 24 hours after injection, without needing treatment repetition [42].…”

Hyperlipidemia Increases Nalbuphine Brain Accumulation with Multiple Dosing without Affecting Its Analgesic Response—Its Respiratory Depression Potential Should Be Investigated in Future Studies

“…This model has been extensively used in hyperlipidemia research mainly because it produces marked hyperlipidemia (within 24 h) via inhibition of lipoprotein lipase and indirect stimulation of 3-hydroxy-3-methylglutaryl coenzyme A [ 15 , 17 , 20 ]. It should be noted that several reports have shown an absence of poloxamer-induced hepatotoxicity when poloxamer is administered in a single-dose regimen in contrast to the chronic poloxamer 407 model of hyperlipidemia [ 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. After 1 mg/kg i.p.…”