Fodipir and Its Dephosphorylated Derivative Dipyridoxyl Ethyldiamine Are Involved in Mangafodipir-Mediated Cytoprotection against 7 beta-Hydroxycholesterol-Induced Cell Death
2013 (English)In: Pharmacology, ISSN 0031-7012, E-ISSN 1423-0313, Vol. 92, no 3-4, 182-186 p.Article in journal (Refereed) Published
Objective: Mangafodipir exerts pharmacological effects, including vascular relaxation and protection against oxidative stress and cell death induced by oxysterols. Additionally, mangafodipir has been proposed for cardiovascular imaging. The primary metabolites of mangafodipir, manganese dipyridoxyl ethyldiamine (MnPLED) and its constituent dipyridoxyl diphosphate (Dp-dp) also known as fodipir, are pharmacologically active. However, whether they affect oxysterol-induced cytotoxicity is currently unknown. In this study, we examine whether the mangafodipir metabolite affects 7 beta-hydroxycholesterol (7 beta-OH)-induced cell death and identify the underlying mechanisms. Methods: U937 cells were pretreated or not with mangafodipir substrate (Ms; 200 pm), MnPLED (100 mu mol/l) or Dp-dp (100 mu mol/l) for 8 h and then exposed to 7 beta-OH (28 mu mol/l) for 18 h. Results: Our results revealed that pretreatment with MnPLED or Dp-dp protected against 7 beta-OH-induced cellular reactive oxygen species (ROS) production, apoptosis, and lysosomal membrane permeabilization (LMP). MnPLED and Dp-dp, in par with Ms, confer protection against 7 beta-OH-induced cytotoxicity by reducing cellular ROS and stabilization of the lysosomal membrane. Conclusion: These results suggest that fodipir is the pharmacologically active part in the structure of mangafodipir, which prevents 7 beta-OH-induced cell death by attenuating cellular ROS and by preventing LMP. In addition, MnPLED, which is the dephosphorylated product of fodipir, exerts a similar protective effect against 7 beta-OH-induced cytotoxicity. This result indicates that dephosphorylation of fodipir does not affect its pharmacological actions. Altogether our result confirms the cytoprotective effect of mangafodipir and justifies its potential use as a cytoprotective adjuvant.
Place, publisher, year, edition, pages
KARGER, ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND , 2013. Vol. 92, no 3-4, 182-186 p.
Atherosclerosis, Apoptosis, Mangafodipir, Oxidative stress, Oxysterols
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-102098DOI: 10.1159/000354601ISI: 000326770700008OAI: oai:DiVA.org:liu-102098DiVA: diva2:668377
Funding Agencies|Swedish Heart Lung Foundation||Torsten and Ragnar Soderberg Foundation||Stroke Foundation||Olle Engkvist Foundation||Swedish Gamla Tjanarinnor Foundation||Linkoping University Linkoping University Hospital Research Foundation||Medical Research Council of Southeast Sweden||2013-11-292013-11-292013-11-29