Xanthine oxidoreductase (XOR) catalyzes the final step of purine metabolism from xanthine to urate. XOR is then converted into xanthine oxidase (XO), incurring tissue damage when XO after XOR is activated such as in diabetes. The aim of this study is to evaluate the pathogenic role of XOR/XO in the development of diabetic polyneuropahty (DPN), and to clarify whether suppression of XO is beneficial for DPN. C57BL6 (C57) and db/db mice (db) 5-week of age were treated daily with a new potent XO-inhibitor, topiloxostat (To), 1mg/kg (dbT1) and 2mg/kg (dbT2) ad libitum with conventional laboratory chow for 8 weeks. During experimental period, glycemic levels, nerve conduction velocity (NCVs) and tail flick response were regularly monitored. At end, following the measurement of sciatic nerve blood flow (SNBF) by laser doppler, mice were killed for the evaluation of XO activity of the sciatic nerve (SN), intra-epidermal nerve fiber density (IENFD) and Iba-I positive macrophage infiltration (MI) intoSN. Glycemic levels were comparable among all diabetic groups. There was a significant delay of NCVs and elevated perception threshold of tail flick in db compared to C57. To-treatment improved these measures in a dose dependent manner (p<0.dbT2 vs. C57 for NCVs, and p<0.db vs. dbT1 and p<0.01 db vs. dbT2 for tail flick). XO activity in SN was dose-dependently suppressed compared to db (p<0.vs. dbT1, p<0.01 vs. dbT2). To-treatment at a high dose also corrected reduced SNBF and IENFD in db (p<0.01 dbT2 vs. db for both). There was a significant increase in Iba-I positive macrophages in SN of db compared to C57 after 4 week-treatment (p<0.01). MI was significantly suppressed in dbT1 and dbT2 (p<0.01). In contrast, there was no significant difference in MI at 8 week-treatment among all the groups. These results indicated the possible implication of XOR/XO metabolism in the pathophysiology of DPN and To may be a promising compound for the treatment of DPN.


H. Mizukami: Research Support; Self; Sanwa Kagaku Kenkyusho Co., Ltd., Mitsubishi Tanabe Pharma Corporation. R. Koyama: None. K. Takahashi: None. S. Osonoi: None. S. Ogasawara: None. S. Yagihashi: None.

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