A novel class of copper(II)- and zinc(II)-bound non-steroidal anti-inflammatory drugs that inhibits acute inflammation in vivo

Abstract

BackgroundThe ability of Zn(II) and Cu(II) metal complexes of non-steroidal anti-inflammatory drugs (NSAIDs) to inhibit acute arterial inflammation in vivo has been studied. ResultsWhen acute vascular inflammation was induced in normocholesterolemic New Zealand White rabbits by inserting a non-occlusive silastic collar around the common carotid artery, a single oral dose of Cu(II)-indomethacin (Cu(II)Indo, 3 mg/kg) administered by laparotomy achieved a 67 % (8.2 ± 1.7 vs. 2.7 ± 0.4 image units, p < 0.05) reduction in endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) but did not inhibit endothelial intercellular adhesion molecule (ICAM-1) expression significantly. Treatment with Cu(II)-acemetacin (Cu(II)ACM, 3 mg/kg) led to a profound 88 % (8.2 ± 1.7 vs. 1.0 ± 0.5 image units, p < 0.01) reduction in endothelial VCAM-1 expression but did not inhibit ICAM-1 expression, while treatment with Zn(II)-acemetacin (Zn(II)ACM, 3 mg/kg) led to an 84 % (19.3 ± 1.0 vs. 3.1 ± 1.2 image units, p < 0.01) reduction in endothelial ICAM-1 expression and did not inhibit VCAM-1 expression. No adverse gastric, hepatic or renal effects were observed in treated animals. ConclusionThese findings provide the “proof of concept” that this novel class of drug, where there is complexation of NSAIDs with metal ions, has substantial anti-inflammatory effects in an animal model of acute vascular inflammation with the possibility of low rates of adverse effects.

CuII(atsm) Attenuates Neuroinflammation

“…Since Cu II (atsm) is known to increase SOD1 copper content in animal models of ALS ( Roberts et al, 2014 ), we hypothesize that the antioxidant reactions raised by Cu II (atsm) may contribute to reducing VCAM-1 expression after systemic LPS challenge. Interestingly, administration of copper-bound anti-inflammatory agents significantly reduces endothelial expression of VCAM-1 after acute injury in rabbits ( Puranik et al, 2016 ). By contrast, an in vitro study has shown that treatment of human aortic endothelial cells with cupric sulfate increases VCAM-1 expression, indicative of increased inflammation ( Wei et al, 2014 ).…”

Metallodrugs are unique: opportunities and challenges of discovery and development

“…Examples are Cu II -acemetacin and Zn II -indomethacin which inhibit acute arterial inammation in in vivo rabbit studies analysing VCAM-1 and ICAM-1 expression. 154 Halfsandwich electron-decient Os II , Ir III and Ru II carborane complexes (Os7, Ir8 †, Ru10 †) inhibit lipopolysaccharideinduced nitric oxide production, a known anti-inammatory response, without cytotoxicity. 155 In vitro screening techniques can be used to assess anti-inammatory activity.…”

Copper(II) complexes of coumarin-derived Schiff base ligands: Pro- or antioxidant activity in MCF-7 cells?

“…b Calculated isotropic values via the equation g o = (g x +g y +g z )/3. 3,25,20 CuSO 4 >100* * IC 50 values from reference 20. These values were measured in the same laboratory as those reported for the current work using the same cell line…”

“…24 In addition, copper(II) complexes of clinically used non-steroidal anti-inflammatory drugs (NSAIDs) are often more potent anti-inflammatory agents than either the parent NSAID drug or the uncomplexed copper salt. 25,26 Thus the role of copper complexes, in both the generation of and amelioration of, ROS has been established in a number of models and studies.…”