Evaluation of teratogenic potential of Stobadin at different gestational stages in rats

Abstract

The pyridoindole derivative stobadine [(−)-cis-2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido (4,3b)indole] has been described as a drug with antihypoxic and antiarrhythmic cardioprotective properties. Here its reactivity with peroxyl radicals in liposomes using a lipid-soluble azo-initiator of peroxyl radicals, 2,2'-azo-bis(2,4-dimethyl-valeronitrile) (AMVN), was examined. Stobadine exerted scavenging as evidenced by the inhibition of: (i) cis-parinaric acid fluorescence decay (half-maximal effect at 20μM), or (ii) luminol-sensitized chemiluminescence (half-maximal effect at 33 μM). In rat liver mu;somes, stobadine was equally efficient in inhibiting lipid peroxidation induced by lipid-soluble (AMVN) or water-soluble 2,2'-azo-bis(2-aminopropane)-HCl (AAPH), azo-initiators of peroxyl radicals with half-maximal effect at 17 μM. Stobadine partitions in a two-phase system (octanol-water) with the coefficient log P = 0.57 ± 0.03, explaining its ability to quench peroxyl radicals in both lipid and aqueous phases. Stobadine is not an efficient scavenger of Superoxide radicals. The second order rate constant for the reaction of stobadine with Superoxide was estimated to be 7.5 × 102 M−1 sec−1 as measured by superoxide-induced lucigenin-amplified chemiluminescence. ESR measurements showed that stobadine in liposomes does not reduce the chromanoxyl radical of a vitamin E homologue with a 6-carbon side-chain, 2,5,7,8-tetramethyl-2-(4'-methylpentyl)chroman-6-ol (chromanol-α-C6), in agreement with pulse-radiolysis results obtained using Trolox in homogeneous solution (Steenken et al., Chem Res Toxicol5: 355–360, 1992). Stobadine increased the magnitude of the chromanoxyl and ascorbyl radical ESR signal generated by lipoxygenase + arachidonate. This was interpreted to be due to the interaction of stobadinyl radicals with the chromanol ring and ascorbate, respectively. It is suggested that high reactivity of stobadine radicals requires the presence of reducing antioxidants (vitamin E, vitamin C) to exhibit its antioxidant effects in physiological systems.