N,N '-diacetyl-L-cystine (DiNAC), the disulphide dimer of N-acetylcysteine, inhibits atherosclerosis in WHHL rabbits: Evidence for immunomodulatory agents as a new approach to prevent atherosclerosis
M. Wagberg et al., N,N '-diacetyl-L-cystine (DiNAC), the disulphide dimer of N-acetylcysteine, inhibits atherosclerosis in WHHL rabbits: Evidence for immunomodulatory agents as a new approach to prevent atherosclerosis, J PHARM EXP, 299(1), 2001, pp. 76-82
Citations number
38
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Oxidation of lipoprotein-derived lipids is generally accepted to be importa
nt in atherogenesis, and lipophilic antioxidants have been suggested as pot
ential antiatherosclerotic agents. The antiatherogenic effects observed by
certain antioxidants, especially probucol, in different animal models suppo
rt this suggestion. There are however also cases where other lipophilic ant
ioxidants have not been able to support this hypothesis. This has raised th
e question whether the effects of probucol and similar compounds are mainly
due to some other property, unrelated to their antioxidant efficacy. For e
xample, probucol is shown to possess immunomodulatory properties. Immune re
actions are known to occur during atherogenesis. We therefore tested the di
mer of N-acetylcysteine, DiNAC, which is a disulfide with immunomodulating
properties and enhances oxazolone-induced contact sensitivity (CS) reaction
s in mice, for effects on atherosclerosis. When given to male heritable hyp
erlipidemic rabbit (WHHL) rabbits from 10 to 22 weeks of age, this compound
reduced by 50% thoracic aorta atherosclerosis (p < 0.05), without affectin
g plasma lipid levels. Here we also show that probucol and a close chemical
analog, both known to prevent atherosclerosis in WHHL rabbits, enhance the
CS reaction in mice, while two other related antioxidants did not affect t
he CS reaction. At least one of these is also without effect on atheroscler
osis in WHHL rabbits. The results show that DiNAC might represent a new tre
atment modality for atherosclerosis-related disease, and suggest that some
antioxidants may have antiatherosclerotic properties more related to "immun
omodulatory" properties than to antioxidant properties in general.