Unique organoprotective properties of a novel IH636 grape seed proanthocyanidin extract on cadmium chloride-induced nephrotoxicity, dimethylnitrosamine (DMN)-induced splenotoxicity and MOCAP-induced neurotoxicity in mice

Several observations, both in humans and laboratory animals, have suggested that proanthocyanidins exhibit a broad spectrum of pharmacological, therap eutic and chemoprotective properties. Specifically, some of our earlier stu dies have shown that IH636 grape seed proanthocyanidin extract (GSPE, comme rcially known as ActiVin (R)) provides excellent concentration- and dose-de pendent protection against toxicities induced by diverse agents, such as ac etaminophen, hydrogen peroxide, 12-O-tetradecanoylphorbol-13-acetate (TPA), smokeless-tobacco extract, idarubicin and 4-hydroxyperoxycyclophosphamide in both in vitro and in vivo models. In some models, GSPE proved to be a be tter cytoprotectant than vitamins C, E and beta -carotene. The purpose of t his investigation was three fold: (i) to indirectly assess the bioavailabil ity of GSPE in multiple target organs, (ii) quantify GSPE's capacity to ave rt cadmium chloride (CdCl2)-induced nephrotoxicity, dimethylnitrosamine (DM N)-induced splenotoxicity and O-ethyl-S,S-dipropyl phosphorodithioate (MOCA P)-induced neurotoxicity, and lastly (iii) to evaluate possible mechanisms of protection in mice. In order to determine all these, three separate expe riments were designed and each experiment consisted of four groups, such as vehicle control, GSPE alone, toxicant alone and GSPE + toxicant. GSPE was administered orally (100 mg/Kg) for 7-8 days prior to the toxicant exposure . Parameters of the analyses included evaluation of serum chemistry changes (ALT, BUN and CK), histopathology and integrity of genomic DNA, both quant itatively and qualitatively. Results indicate that GSPE preexposure prior t o cadmium chloride and DMN provided near complete protection in terms of se rum chemistry changes (ALT, BUN and CK) and inhibition of both forms of cel l death, e.g., apoptosis and necrosis. DNA damage, a common denominator usu ally associated with both apoptosis and necrosis was significantly reduced by GSPE treatment. Histopathological examination of organs correlated stron gly with the changes in serum chemistry and the DNA modification data. Surp risingly, MOCAP exposure showed symptoms of neurotoxicity coupled with seru m chemistry changes in the absence of any significant genomic DNA damage or brain pathology. Although, GSPE appeared to partially protect the neural t issue, it powerfully antagonized MOCAP-induced mortality. Taken together, t his study suggests that in vivo GSPE-preexposure may protect multiple targe t organs from a variety of toxic assaults induced by diverse chemical entit ies.