Naringenin ameliorates diabetic neuropathic pain by modulation of oxidative-nitrosative stress, cytokines and MMP-9 levels

Abstract

Diabetes mellitus is a serious debilitating epidemic affecting all social strata, imposing huge health, social and economic burdens. Diabetic neuropathic pain, an important microvascular complication of diabetes mellitus, characterized by allodynia and hyperalgesia, is recognized as one of the most difficult types of pain to treat. The development of tolerance, inadequate relief and potential toxicity of classical antinociceptives warrant the investigation of newer agents to relieve this pain. Reactive oxygen/nitrogen species, cytokines and matrix metalloproteinases (MMPs) are implicated in the pathogenesis of diabetic neuropathy. The present study was designed to explore the effect of naringenin, a citrus flavonoid, on streptozotocin induced diabetic neuropathic pain in Wistar rats. After 8 weeks of diabetes induction, rats developed neuropathy which was evident from marked hyperalgesia and allodynia associated with enhanced oxidative-nitrosative stress, release of inflammatory mediators (TNF-α, TGF-1β), MMP-9 activation and decreased motor nerve conduction velocity. Treatment with naringenin (25, 50, 100 mg kg⁻¹) for 4 weeks starting from the 5th week of streptozotocin injection significantly attenuated behavioral, biochemical and molecular changes, along with alterations in motor nerve conduction velocity in a dose-dependent manner. Moreover, diabetic rats treated with insulin-naringenin combination produced a more pronounced effect as compared to individual drugs. The major finding of the study is that insulin alone corrected the hyperglycemia and partially reversed the pain response in diabetic rats. However, combination with naringenin not only attenuated the diabetic condition but also reversed neuropathic pain through modulation of oxidative–nitrosative stress, inflammatory cytokine release and MMP inhibition in the diabetic rats. Modulation of MMP-9 by a natural flavonoid like naringenin seems to be a novel approach to target diabetic neuropathic pain.