Effects of Polyphenols from Seed Shells of Japanese Horse Chestnut (Aesculus turbinata BLUME) on Methotrexate-Induced Intestinal Injury in Rats

Abstract

ABSTRACT. The purpose of this study was to evaluate the effects of polyphenols from seed shells of Japanese horse chestnut (JHP) on methotrexate (MTX)-induced intestinal injury in rats. MTX application caused intestinal morphological injury and increase in malondialdehyde (MDA) levels, decrease in levels of glutathione (GSH) and glutathione peroxidase (GSH-Px) activities in small intestine. However, oral administration of JHP ameliorated MTX-induced intestinal injury and inhibited the increase in MDA and the decrease in GSH and GSH-Px activity in small intestine. In conclusion, our results indicated that oral administration of JHP alleviated MTX-induced intestinal injury through its antioxidant properties. The seeds of the Japanese horse chestnut (Aesculus turbinata BLUME) have been utilized as an emergency provision since ancient times. Nowadays, after treating them with wood ashes to remove bitter saponins, edible seeds are being used as ingredients of traditional foods like rice balls and rice cake in Japan. The biological activities of the seed shell ingredients of the Japanese horse chestnut, which have been waste products for the preparation of edible seeds, have become a focus of study [17,18,26]. Recently, Ogawa et al. have reported that seed shells contain higher levels of polyphenolic antioxidants [26]. The predominant polyphenolic compounds from seed shells of the Japanese horse chestnut are highly polymeric proanthocyanidins having doubly-linked A-type interflavan linkages as well as singlylinked B-type bonds without gallic acid esterified to them [26].Methotrexate (MTX), a structural analogue of folic acids, is widely used as a chemotherapeutic drug in the treatment of leukemia and other malignancies [15]. Being a high affinity inhibitor of dihydrofolate reductase, MTX is a prooxidant compound that causes depletion of the dihydrofolate pool and directly affects the synthesis of thymidilate, suppressing DNA synthesis [15,19]. Since the cytotoxic effect of MTX is not selective for cancer cells, it also affects normal tissue that have a high rate of proliferation, such as the gut mucosa. Thus, the efficacy of MTX is often limited by severe side effects such as intestinal injury [1,7,15,31]. MTX-induced intestinal injury results in malabsorption syndrome through serious malabsorption of nutrients and diarrhea [1,28].Reactive oxygen species (ROS) are implicated in the pathogenesis of the MTX-induced gastrointestinal mucosal injury [11]. It was also demonstrated that MTX caused a significant reduction in antioxidant protein and enzyme levels and an increase in levels of oxidant markers such as malondialdehyde (MDA) [12,16,25,29]. Therefore, In order to minimize side-effects of MTX in patients, the studies focused on antioxidants [12,16,25,29,32].Many polyphenols are known to be antioxidants, and the possibility exists that they protect against oxidative damage by directly neutralizing reactive oxidants [8,14,21,22,24,30]. However, to our knowledge, there are no reports showing the protective effects of po...

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