Cobinamide is a strong and versatile antioxidant that overcomes oxidative stress in cells, flies, and diabetic mice

Abstract

Increased oxidative stress underlies a variety of diseases, including diabetes. Here we show that the cobalamin/vitamin B12 analog cobinamide is a strong and multi-faceted antioxidant, neutralizing superoxide, hydrogen peroxide, and peroxynitrite, with apparent rate constants of 1.9 × 108, 3.7 × 104, and 6.3 × 106 M−1 s−1, respectively for cobinamide with the cobalt in the + 2 oxidation state. Cobinamide with the cobalt in the + 3 oxidation state yielded apparent rate constants of 1.1 × 108 and 8.0 × 102 M−1 s−1 for superoxide and hydrogen peroxide, respectively. In mammalian cells and Drosophila melanogaster, cobinamide outperformed cobalamin and two well-known antioxidants, imisopasem manganese and manganese(III)tetrakis(4-benzoic acid)porphyrin, in reducing oxidative stress as evidenced by: (i) decreased mitochondrial superoxide and return of the mitochondrial membrane potential in rotenone- and antimycin A-exposed H9c2 rat cardiomyocytes; (ii) reduced JNK phosphorylation in hydrogen-peroxide-treated H9c2 cells; (iii) increased growth in paraquat-exposed COS-7 fibroblasts; and (iv) improved survival in paraquat-treated flies. In diabetic mice, cobinamide administered in the animals’ drinking water completely prevented an increase in lipid and protein oxidation, DNA damage, and fibrosis in the heart. Cobinamide is a promising new antioxidant that has potential use in diseases with heightened oxidative stress.

The Antioxidant/Nitric Oxide-Quenching Agent Cobinamide Prevents Aortic Disease in a Mouse Model of Marfan Syndrome

“…The cobinamide-treated mice appeared normal and gained weight just as untreated mice, similar to our previous results in Prkg1 R177Q/+ mice and diabetic mice. 35 , 36 The only laboratory abnormality in the cobinamide-treated mice was an increase in peripheral blood monocytes, reaching significance in the mutant mice; the clinical implications of this are unclear, particularly because we found no increase in monocytic infiltration into the aorta. In rats, we found cobinamide had a serum half-life of ∼11 hours after oral administration.…”

“… 47 This is consistent with our previous results in mice treated with similar cobinamide concentrations in the drinking water. 36 …”

“…The cobalamin (vitamin B 12 ) analog cobinamide is a powerful antioxidant, serving as both a superoxide dismutase and catalase mimetic, thereby neutralizing O 2 · - and H 2 O 2 , respectively 36 (cobinamide structure is shown in Supplemental Figure 1 ). In addition, cobinamide reacts with ·NO and ONOO-.…”

“…In addition, cobinamide reacts with ·NO and ONOO-. 36 , 37 We, therefore, hypothesized that cobinamide could be an effective treatment for MFS, and tested it in Fbn1 C1041G/+ mutant male and female mice, assessing histopathology, oxidative stress markers, PKG activity, and aortic size.…”

Acute rotenone poisoning: A scoping review

“…Since rotenone can increase oxidative stress in cells ( Fig. 1 B), it seems possible that an agent which neutralizes reactive oxygen species could be useful in treating rotenone poisoning [ 4 , 7 , [32] , [33] , [34] ]. Testing of such agents in animal models would appear indicated.…”