Neuropathy induced by exogenously administered advanced glycation end-products in rats.
Aims/Introduction:  Advanced glycation end-products (AGE) have been implicated in the development of diabetic neuropathy. It still remains unknown, however, how AGE cause functional and structural changes of the peripheral nerve in diabetes. To explore the role of AGE in diabetic neuropathy, we examined the peripheral nerve by injecting AGE into normal Wistar rats.


METHODS
Young, normal male Wistar rats were injected intraperitoneally (i.p.) daily for 12 weeks with purified AGE prepared by incubating D-glucose with bovine serum albumin (BSA). A control group received BSA alone. A group of rats given AGE were co-treated with aminoguanidine (50 mg/kg/day, i.p.). Peripheral nerve function and structure, as well as nerve Na(+),K(+)-ATPase activity, were examined in these rats. Immunohistochemical expressions of 8-hydroxy-2'-deoxyguanosine (8OHdG) and nuclear factor-κB (NF-κB)p65 were also examined.


RESULTS
Serum AGE levels were increased two to threefold in the AGE-treated group compared with those in the BSA-treated control group. AGE-treated rats showed a marked slowing of motor nerve conduction velocity (MNCV) and decreased nerve Na(+),K(+)-ATPase activity compared with those in the BSA-treated group. These changes were accompanied by intensified expressions of 8OHdG and NF-κBp65 in endothelial cells and Schwann cells. Aminoguanidine treatment corrected MNCV delay, Na(+),K(+)-ATPase activity, and suppressed the expression of 8OHdG and NF-κB, despite there being no influence on serum AGE levels.


CONCLUSIONS
The results suggest that an elevated concentration of blood AGE might be one of the contributing factors to the development of neuropathic changes in diabetes.
Department of Pathology and Molecular Medicine, Graduate School of Medicine, Hirosaki University, Hirosaki.
Yusuke
Y
Nishizawa
Department of Pathology and Molecular Medicine, Graduate School of Medicine, Hirosaki University, Hirosaki.
Ryu-Ichi
R
Wada
Division of Neurology, Aomori Prefectural Hospital, Aomori.
Masayuki
M
Baba
Department of Pathophysiological Science, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.
Masayoshi
M
Takeuchi
Department of Pathology and Molecular Medicine, Graduate School of Medicine, Hirosaki University, Hirosaki.
Chieko
C
Hanyu-Itabashi
Department of Pathology and Molecular Medicine, Graduate School of Medicine, Hirosaki University, Hirosaki.
Soroku
S
Yagihashi
Advanced glycation end‐products; Neuropathy; Oxidative stress