The Effect of Ibuprofen and L.Arginine on a Murine Model of Diabetic Neuropathy & study of the possible mechanisms

Abstract

Diabetic neuropathy (DN) is the most common complication of diabetes mellitus (DM), affecting as many as 50% of patients with type 1 and type 2 DM. Diabetic peripheral neuropathy involves the presence of symptoms and /or signs of peripheral nerve dysfunction in diabeticsafter other possible causes have been excluded. It is the most common form of neuropathies in the developed countries and the leading cause for non-traumatic amputations. DN is a form of chronic neuropathic pain, where pain stimulus is related to the effects of hyperglycemia on the nerve and vasculature. Ibuprofen-L-arginine exerts antinociceptive effects on mechanical allodynia induced by chronic constriction injury (CCI). L-Arginine alone exerts no antinociceptive effects on mechanical allodynia in CCI. The present study was designed to assess the antiallodynic effects of ibuprofen and L-arginine in a rat model of diabetic neuropathy and to further confirm the role of NO &TNF alpha in these effects. 5 groups of female Wister rats, 10 rats each,were used in the present study: a naïve group,STZ induced diabetic group, and the three treated groups,ibuprofen 100mg, L-Arginine 100mg anda combinedibuprofen + L-Arginine group 100mg each.The duration of the study wasfive weeks starting by induction of type 1 DM by single IP injection of STZ (50 mg / kg). One week later, Summary and Conclusion 160 after establishment of type 1 DM, treatment of each group with the corresponding drug was started by daily oral gavage. Assessment of mechanical allodynia was carried out weekly in different groups by the use of von Frey filaments applied to the right hind paw.At the end of the fifthweek, rats were killed by decapitation, TNF-α and NO levels in spinal cord werebiochemically assessed. In addition, theexpression of miRNA-155 was tested in different groups. Epidermal thickness of foot pad and muscle fiber diameter was quantified by image analysis. Ibuprofen treated group showed a significant decrease of the mechanical allodynia in comparison to the STZ induced diabetic non-treated group in the third and fourth weeks after drug administration and its anti-allodynic effect was slightly stronger than that of L-arginine alone or ibuprofen + L-arginine group, which showed a significant decrease of the mechanical allodynia at the fourth week only. These findings run in accordance with the histological studies of muscle fiber diameter & epidermal thickness, which were found to decrease in the STZ diabetic neuropathic group & re-increase with treatments.Further, there were significant increase in the spinal NO leveland miRNA-155 in STZ diabetic neuropathic group.Ibuprofen treated group showed a significant decrease of both parameters in comparison to the STZ diabetic group and its effect was stronger than that of LArginine alone or ibuprofen + L-Arginine.