Bradykinin B1 antagonism inhibits oxidative stress and restores Na+K+ ATPase activity in diabetic rat peripheral nervous system |
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| Institution: | 1. Departamento de Biologia, Universidad Argentina John F. Kennedy, Buenos Aires, Argentina;2. Escuela de Medicina y Odontologia, USAL, Buenos Aires, Argentina;3. CHUL Research Center, Laval University, Quebec, Canada;1. Discovery Biology, Bristol-Myers Squibb, Inc., 5 Research Parkway, Wallingford, CT 06492 USA;2. Lead Discovery and Optimization, Bristol-Myers Squibb, Inc., 5 Research Parkway, Wallingford, CT 06492 USA;3. Discovery Chemistry, Bristol-Myers Squibb, Inc., 5 Research Parkway, Wallingford, CT 06492 USA;3. From the Norwegian Centre for Movement Disorders, Stavanger University Hospital, 4068 Stavanger, Norway,;4. the Centre for Organelle Research, University of Stavanger, 4036 Stavanger, Norway,;5. the European Synchrotron Radiation Facility, 38000 Grenoble, France,;6. the Department of Medical Biochemistry, Stavanger University Hospital, 4068 Stavanger, Norway, and;1. Institut de Radioprotection et de Sûreté Nucléaire, Laboratoire Expérimentation Environnement et Chimie IRSN/L2EC, CEN Cadarache, 13115 St-Paul-Lez-Durance, France;2. Université Clermont Auvergne, CNRS, SIGMA Clermont, Institut de Chimie de Clermont-Ferrand, F-63000 Clermont-Ferrand, France;3. CNRS, UMR 6296, ICCF, Equipe Photochimie, BP 80026, F-63171 Aubière, France;4. Nexans Research Center, 29 rue du Pré Gaudry, 69353 Lyon Cedex 07, France |
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| Abstract: | Diabetic peripheral neuropathy is one the most common complications of diabetes mellitus and frequently results in clinically significant morbidities such as pain, foot ulcers and amputations. The diabetic condition progresses from early functional changes to late, poorly reversible structural changes. The chronic hyperglycemia measured alongside diabetes development is associated with significant damage and failure of various organs. In the present study diabetes was induced in male Wistar rats by a single dose of streptozotocin (STZ) and the association between the BKB1-R and the oxidative stress and Na+-K+ ATPase activity in nervous tissues was analysed. The results showed that the resulting hyperglycemia induced a reduction of the neuronal electrical function integrity and increased oxidative stress in the sciatic nerve homogenates of 30 days diabetic rats. Malondialdehyde (MDA) used as a marker of oxidative stress was elevated whereas Biological Antioxidant Potential (BAP), glutathion (GSH) levels and superoxide dismutase (SOD) activity were decreased. Treatment of the rats 3 days before the end of the 4 week period with the BKB1 antagonist R-954 restored the neuronal activity and significantly attenuated the oxidative stress as shown by the level of the various markers returning close to levels found in control rats. Our results suggest that the BKB1-R subtype is overexpressed in sciatic nerve during the STZ-induced diabetes development as evidenced by inhibitory effects of the BKB1-R antagonist R-954. The beneficial role of BKB1-R antagonist R-954 for the treatment of diabetic neuropathy is also suggested. |
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