561-P: Activated Xanthine Oxidase in Serum Is a Potent Therapeutic Target for Experimental Diabetic Polyneuropathy

Abstract

Xanthine oxidase (XO), a potent inducer of reactive oxygen species, catalyzes purine metabolism. XO is expected to be implication of the macrophage activation. XO is also expressed in the peripheral nerve system, while its role in diabetic polyneuropathy (DPN) has not been clarified. We explored the implication of XO in DPN of db/db mice (db/db) treating with XO-inhibitor, topiloxostat (To). C57BL6 mice (C57) and db/db (5 wks of age) were daily treated with 1mg/kg (dbT1) and 2mg/kg (dbT2) To (per os) for 8 wks. During experimental period, peripheral nerve function was monitored. At end, serum and dissected sciatic nerves and dorsal root ganglia (DRG) served for evaluation of uric acid metabolism. Primary culture of DRG neuron was performed to evaluate the effects of To on neurite outgrowth in vitro. To improved significant delay of nerve conduction velocities and elevation of threshold for tail flick test in db/db in a dose dependent manner (p<0.05 dbT2 vs. C57 for NCVs, p<0.05 db/db vs. dbT1, p<0.01 db/db vs. dbT2 for tail flick). XO activity was significantly up-regulated in DRG (p<0.01) and serum of db/db compared to those of W (p<0.05). To successfully suppressed the elevated XO activity in a dose dependent manner (p<0.05, W vs. T1, p<0.01, T1 vs. T2). Uric acid was significantly accumulated in serum and DRG of db/db compared to those of C57 (p<0.05). To could significantly reduce the accumulation (p<0.01). In primary culture of DRG neuron, extrinsic 100 μM XO depleted the neurite outgrowth more than 50 % than that of non-stimulated neurons (p<0.01). 4.3ng/ml To could significantly restored the reduction of neurite outgrowth compared to that of non-treated neurons (p<0.05). As a conclusion, increase in XO activity in serum and DRG may be implicated in the pathophysiology of DPN in db/db. Activation of XO in serum may directly exacerbate neuronal injury for DRG in DPN. To has a beneficial effect on DPN through its specific property to suppress serum XO activity. Disclosure H. Ichinohe: None. H. Mizukami: None. S. Osonoi: None. K. Kudo: None. S. Yagihashi: None.