Inhibition of the development of experimental diabetic neuropathy by suppression of AGE formation with a new antiglycation agent

Abstract

Non-enzymatic glycation of neural proteins and their endproducts (AGE) have been implicated in the pathogenesis of diabetic neuropathy. We examined the effects of OPB-9195 (OPB) [(±)-2-isopropylidenehydrazono-4-oxothiazolidin-5-ylacetanilide, Otsuka Pharmaceutical, Japan], a new inhibitor of glycation, on the peripheral nerve structure and function in diabetic rats. Eight-week-old Wistar rats were made diabetic by streptozotocin (40 mg/kg, iv) and OPB (60 mg/kg/day) was given by gavage for 24 weeks. Age- and sex-matched normal Wistar rats were used for comparison. During the experimental period, diabetic rats showed marked hyperglycemia, reduced body weight and significant delay of motor nerve conduction velocity (MNCV). OPB treatment did not affect the body weight, blood glucose levels and glycated hemoglobin in diabetic rats. At end, delayed MNCV was significantly improved in treated diabetic rats by 60%, and serum AGE levels were reduced. Expression of immunoreactive AGE in the sciatic nerve was reduced in treated diabetic rats compared with those in untreated rats. Sciatic nerve (Na+,K+)-ATPase activity was also restored in treated diabetic rats. On the cross-sectioned sciatic nerves, the cells with oxidative stress-related DNA damage as expressed by 8 hydroxy-2′-deoxyguanosine were significantly reduced in the peripheral nerve of diabetic rats by OPB treatment. The current study thus suggested that OPB is beneficial for the reduction of serum and tissue AGE and for prevention of diabetic neuropathy.