NF-κB inhibitory action of resveratrol: A probable mechanism of neuroprotection in experimental diabetic neuropathy
Introduction
Diabetes is attaining an epidemic stature throughout the world and the scenario in developing nations is worsening day by day. One of the most debilitating and common complication of diabetes is diabetic neuropathy which affects more than 60% diabetics. The clinical manifestations of diabetic neuropathy may include numbness, burning and tingling sensation, intractable pain, etc., [1], [2]. In spite of decades of research in this field there is still no approved therapy for treating diabetic neuropathy. Only few symptomatic treatments are available which lessen the neuropathic pain which is one of cardinal features of diabetic neuropathy. The neuropathy progresses with decreasing nerve functionality and decreasing nerve blood perfusion, which ends up in malnourished nerve and lead to permanent nerve damage [3], [4].
Pathophysiological factors of diabetic neuropathy include persistent hyperglycemia, microvascular insufficiency, oxidative stress, nitrosative stress, PARP over activation, defective neurotrophism, autoimmune-mediated nerve destruction, etc., [1], [5], [6]. The factors like oxidative stress, AGE formation, lipid peroxidation which results from diabetic condition can stimulate inflammatory processes [7]. Diabetic conditions are associated with chronic low-grade inflammation, evidenced by raised surrogate markers of inflammation which include C-reactive protein (CRP), IL-6 and TNF-α. These further contribute to pathogenesis of diabetes and diabetic neuropathy [8]. Many of the major pathophysiological pathways of diabetic neuropathy may converge at a common platform, i.e., NF-κB activation which is the cause of inflammation resulting in tissue injury at various sites [9].
Inflammation is a complex process, but a central mechanism is activation of the NF-κB cascade. Changes in cytokine levels, ROS and AGEs/advanced lipoxygenation end products (ALEs) generated by hyperglycemia, as in diabetic condition leads to NF-κB activation. In transthyretin-related familial amyloidotic polyneuropathy, up-regulation of the p50 NF-κB subunit was found in peripheral nerves [10]. p65 subunit of NF-κB was found to be over expressed in sural nerve macrophages in acute and chronic inflammatory demyelinating polyneuropathies which points towards the role of NF-κB in genesis of inflammatory demyelination [11]. Demyelination is well proven contributor to the conduction deficits seen in clinical as well as in experimental diabetic neuropathy. NF-κB has also been reviewed for its role and contribution in causing various other diseases like cancer, rheumatoid arthritis, atherosclerosis, etc., [12].
Resveratrol (trans-3,4′,5-trihydroxystilbene), a natural polyphenolic, non-flavonoid antioxidant, is a phytoalexin found in many plants including grapes, nuts and berries. There are numerous studies that have documented beneficial effects of resveratrol such as cardiovascular and cancer preventive properties [13], [14]. We have previously reported the beneficial effects of resveratrol in experimental diabetic neuropathy [3], [15]. Resveratrol has shown anti-inflammatory activity and its effect has been documented on SIRT and Nrf2 pathways and effect on COX-2 in various experimental models [13]. We assessed the effect of resveratrol treatment on NF-κB inflammatory cascade in experimental diabetic neuropathy. We also tried to find out whether the NF-κB inhibitory activity contributes to the neuroprotection shown in the rat model of experimental diabetic neuropathy.
The study to evaluate NF-κB activity of resveratrol was performed at two different dose levels (10 and 20 mg/kg) in the STZ induced rat model of diabetic neuropathy. The rationale of dose selection was based on our previous study in which we found the effectiveness of resveratrol treatment at theses two doses. As resveratrol is having antioxidant effect we evaluated lipid peroxidation in sciatic nerves. We also studied nerve levels of inflammatory mediators (TNF-α and IL-6 levels). COX-2 has been implicated in causing inflammation and its resolutions, so we investigated the effect of resveratrol treatment on COX-2 levels in experimental diabetic neuropathy. For studying the NF-κB activity we performed the expression studies of NF-κB, IκB-α and p-IκB-α levels in sciatic nerve.
Section snippets
Induction of diabetes and experimental design
The experiments were performed in accordance with regulations specified by the Institute Animal Ethics Committee (IAEC), NIPER. Male Sprague–Dawley rats (250–270 g) were used for the study and were fed on standard rat diet and water ad libitum. Diabetes was induced by streptozotocin (STZ) at a dose of 55 mg/kg (i.p.). Blood samples were collected from tail vein 48 h after STZ administration. The rats with blood glucose more than 250 mg/dl were considered as diabetics and were further considered for
Effect of resveratrol on plasma glucose
After 48 h of streptozotocin there was 4–5 folds increase in blood glucose levels. Resveratrol treatment did not show any change on elevated glucose levels in diabetic rats. At both levels the plasma glucose levels were almost comparable with those of diabetic group. The elevated glucose level is the starting point of all the pathophysiological consequences leading to development and progression of diabetic neuropathy (Table 1).
Effect of resveratrol on functional parameters
Eight weeks of diabetes resulted in significant decrease (p < 0.001)
Discussion
Diabetic neuropathy develops and progresses within 6 weeks in animals injected with streptozotocin as evidenced by decreased MNCV and NBF. The sensory alteration is also well known phenomenon which develops in diabetic animals. Apart from functional and behavioral alteration there exists many biochemical changes like depletion of antioxidant enzymes, enhanced lipid peroxidation, peroxynitrite generation, etc., that accompany diabetic neuropathy [4], [6]. In our previous reports we reported the
Acknowledgments
The authors would like to thank Department of Science and Technology, New Delhi, India for supporting this research project via their FAST Track fellowship sanctioned to Mr. Ashutosh Kumar (SR/FT/LS 89/2009). Authors would also like to acknowledge Department of Pharmaceuticals, Ministry of Chemical and Fertilizers, Government of India for providing partial financial support for this research work.
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