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Ameliorative potential of rutin in combination with nimesulide in STZ model of diabetic neuropathy: targeting Nrf2/HO-1/NF-kB and COX signalling pathway

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Abstract

Emerging role of Nrf-2/HO-1 in pathogenesis of diabetic neuropathy has been suggested. Diabetic neuropathy is one of the most common complications of diabetes and more than 50% patients of diabetes develop diabetic neuropathy. Rutin has been well documented to show protective effect in various complications, e.g., diabetic neuropathy. However, its mechanistic insight is still not completely understood. The present study has been designed to explore the protective effect of rutin and its interaction with COX-2 inhibitor, nimesulide in diabetic neuropathy. DN (diabetic neuropathy) rats were maintained with or without rutin (100 and 200 mg/kg), nimesulide (5 and 10 mg/kg), and their combinations for 8 weeks. Body weight, serum glucose, pain assessment (mechanical allodynia, cold allodynia, mechanical hyperalgesia, and thermal hyperalgesia), and motor nerve conduction velocity (MNCV) were measured in all groups. Oxidative damage was assessed through biochemical estimation and mitochondrial ROS production, followed by inflammatory and apoptotic markers (TNF-α, caspase-3, Nrf-2, HO-1, and NF-kBp65) for their activity, protein, and gene expression. The structural changes were also reported through transmission electron microscope. Streptozotocin injection (55 mg/kg) induced diabetes reduced body weight, reduced the threshold for pain in various pain assessment parameters. Oxidative damage (increased MDA, decreased SOD, catalase, and GSH levels) increased mitochondrial ROS production followed by increased expression of inflammatory markers and decreased expression of Nrf-2/HO-1 in sciatic nerve. Treatment with rutin (100 and 200 mg/kg) and nimesulide (5 and 10 mg/kg) significantly attenuates these alterations as compared to DN control rats. Furthermore, combination of rutin (200 mg/kg) and nimesulide (10 mg/kg) significantly potentiated their protective effect which was significant as compared to their effect alone in streptozotocin-treated rats. The present study suggests the involvement of Nrf-2/HO-1 pathway in the protective effect of rutin against streptozotocin-induced diabetic neuropathy.

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References

  • Agca CA, Tuzcu M, Hayirli A, Sahin K (2014) Taurine ameliorates neuropathy via regulating NF-kappaB and Nrf2/HO-1 signaling cascades in diabetic rats. Food Chem Toxicol 71:116–121

    Article  PubMed  CAS  Google Scholar 

  • Ahmed SM, Luo L, Namani A, Wang XJ, Tang X (2017) Nrf2 signaling pathway: pivotal roles in inflammation. Biochim Biophys Acta 1863:585–597

    Article  PubMed  CAS  Google Scholar 

  • Azevedo MI et al (2013) The antioxidant effects of the flavonoids rutin and quercetin inhibit oxaliplatin-induced chronic painful peripheral neuropathy. Mol Pain 9:53

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Berrocoso E et al (2011) Evaluation of milnacipran, in comparison with amitriptyline, on cold and mechanical allodynia in a rat model of neuropathic pain. Eur J Pharmacol 655:46–51

    Article  PubMed  CAS  Google Scholar 

  • Bhakkiyalakshmi E, Sireesh D, Rajaguru P, Paulmurugan R, Ramkumar KM (2015) The emerging role of redox-sensitive Nrf2–Keap1 pathway in diabetes. Pharmacol Res 91:104–114

    Article  PubMed  CAS  Google Scholar 

  • Bing L, Shujun L, Lining M, Lu C (2012) Prevention of diabetic complications by activation of Nrf-2: diabetic cardiomyopathy and nephropathy. Exp Diabetes Res 2012:1–7

    Google Scholar 

  • Cardozo LF et al (2013) Nutritional strategies to modulate inflammation and oxidative stress pathways via activation of the master antioxidant switch Nrf2. Biochimie 95:1525–1533

    Article  PubMed  CAS  Google Scholar 

  • Chua LS (2013) A review on plant-based rutin extraction methods and its pharmacological activities. J Ethnopharmacol 150:805–817

    Article  PubMed  CAS  Google Scholar 

  • Coppey LJ, Gellett JS, Davidson EP, Dunlap JA, Lund DD, Yorek MA (2001) Effect of antioxidant treatment of streptozotocin-induced diabetic rats on endoneurial blood flow, motor nerve conduction velocity, and vascular reactivity of epineurial arterioles of the sciatic nerve. Diabetes 50:1927–1937

    Article  PubMed  CAS  Google Scholar 

  • Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77

    Article  PubMed  CAS  Google Scholar 

  • Ganesh Yerra V, Negi G, Sharma SS, Kumar A (2013) Potential therapeutic effects of the simultaneous targeting of the Nrf2 and NF-kappaB pathways in diabetic neuropathy. Redox Biol 1:394–397

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ganeshpurkar A, Saluja AK (2017) The pharmacological potential of rutin. Saudi Pharm J 25:149–164

    Article  PubMed  Google Scholar 

  • Gornall AG, Bardawill CJ, David MM (1949) Determination of serum proteins by means of the biuret reaction. J Biol Chem 177:751–766

    PubMed  CAS  Google Scholar 

  • Guerrero L et al (2012) Inhibition of angiotensin-converting enzyme activity by flavonoids: structure-activity relationship studies. PLoS One 7:e49493

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hernandez-Leon A, Fernandez-Guasti A, Gonzalez-Trujano ME (2016) Rutin antinociception involves opioidergic mechanism and descending modulation of ventrolateral periaqueductal grey matter in rats. Eur J Pain 20:274–283

    Article  PubMed  CAS  Google Scholar 

  • Huang Y, Li W, Su ZY, Kong AN (2015) The complexity of the Nrf2 pathway: beyond the antioxidant response. J Nutr Biochem 26:1401–1413

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Je HD et al (2002) Combination of vitamin C and rutin on neuropathy and lung damage of diabetes mellitus rats. Arch Pharm Res 25:184–190

    Article  PubMed  CAS  Google Scholar 

  • Kandhare AD, Raygude KS, Ghosh P, Ghule AE, Bodhankar SL (2012) Neuroprotective effect of naringin by modulation of endogenous biomarkers in streptozotocin induced painful diabetic neuropathy. Fitoterapia 83:650–659

    Article  PubMed  CAS  Google Scholar 

  • Kaspar JW, Niture SK, Jaiswal AK (2009) Nrf 2: INrf2 (Keap1) signaling in oxidative stress. Free Radic Biol Med 47:1304–1309

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • King TE, Ohnishi T, Winter DB, Wu JT (1976) Biochemical and EPR probes for structure-function studies of iron sulfur centers of succinate dehydrogenase. Adv Exp Med Biol 74:182–227

    Article  PubMed  CAS  Google Scholar 

  • Kono Y (1978) Generation of superoxide radical during autoxidation of hydroxylamine and an assay for superoxide dismutase. Arch Biochem Biophys 186:189–195

    Article  PubMed  CAS  Google Scholar 

  • Kuhad A, Chopra K (2009) Tocotrienol attenuates oxidative-nitrosative stress and inflammatory cascade in experimental model of diabetic neuropathy. Neuropharmacol 57:456–462

    Article  CAS  Google Scholar 

  • Kumar A, Mittal R (2017) Nrf2: a potential therapeutic target for diabetic neuropathy. Inflammopharmacol 25:393–402

    Article  CAS  Google Scholar 

  • Li W et al (2008) Activation of Nrf2-antioxidant signaling attenuates NFkappaB-inflammatory response and elicits apoptosis. Biochem Pharmacol 76:1485–1489

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Luck H (1963) Catalase spectrophotometric method. Academic Press, New York

    Google Scholar 

  • Ma S, Liu D, Deng J, Peng Y (2014) Protective effect of mulberry flavonoids on sciatic nerve alloxan-induced diabetic rats. Braj J Pharm Sci 50:765–771

    Article  Google Scholar 

  • Negi G, Kumar A, Joshi RP, Sharma SS (2011a) Oxidative stress and Nrf2 in the pathophysiology of diabetic neuropathy: old perspective with a new angle. Biochem Biophys Res Commun 408:1–5

    Article  PubMed  CAS  Google Scholar 

  • Negi G, Kumar A, Sharma SS (2011b) Melatonin modulates neuroinflammation and oxidative stress in experimental diabetic neuropathy: effects on NF-kappaB and Nrf2 cascades. J Pineal Res 50:124–131

    PubMed  CAS  Google Scholar 

  • Negi G, Kumar A, Sharma SS (2011c) Nrf2 and NF-kappaB modulation by sulforaphane counteracts multiple manifestations of diabetic neuropathy in rats and high glucose-induced changes. Curr Neurovasc Res 8:294–304

    Article  PubMed  CAS  Google Scholar 

  • Negi G, Nakkina V, Kamble P, Sharma SS (2015) Heme oxygenase-1, a novel target for the treatment of diabetic complications: focus on diabetic peripheral neuropathy. Pharmacol Res 102:158–167

    Article  PubMed  CAS  Google Scholar 

  • Niture NT, Ansari AA, Naik SR (2014) Anti-hyperglycemic activity of rutin in streptozotocin-induced diabetic rats: an effect mediated through cytokines, antioxidants and lipid biomarkers. Ind J Exp Biol 52:720–727

    Google Scholar 

  • Palsamy P, Subramanian S (2011) Resveratrol protects diabetic kidney by attenuating hyperglycemia-mediated oxidative stress and renal inflammatory cytokines via Nrf2-Keap1 signaling. Biochim Biophys Acta 1812:719–731

    Article  PubMed  CAS  Google Scholar 

  • Pilat D et al (2016) Blockade of IL-18 signaling diminished neuropathic pain and enhanced the efficacy of morphine and buprenorphine. Mol Cell Neurosci 71:114–124

    Article  PubMed  CAS  Google Scholar 

  • Puka-Sundvall M et al (2000) Impairment of mitochondrial respiration after cerebral hypoxia-ischemia in immature rats: relationship to activation of caspase-3 and neuronal injury. Brain Res Dev Brain Res 125:43–50

    Article  PubMed  CAS  Google Scholar 

  • Quilley J, Santos M, Pedraza P (2011) Renal protective effect of chronic inhibition of COX-2 with SC-58236 in streptozotocin-diabetic rats. Am J Physiol Heart Circul Physiol 300:H2316–H2322

    Article  CAS  Google Scholar 

  • Sameni H, Panahi M (2011) The effect of co-administration of 4-Methylcatechol and Progesterone on sciatic nerve function and neurohistological alterations in streptozotocin-induced diabetic neuropathy in rats. Cell J 13:31–38

    PubMed  PubMed Central  CAS  Google Scholar 

  • Santos-Nogueira E, Redondo Castro E, Mancuso R, Navarro X (2012) Randall-Selitto test: a new approach for the detection of neuropathic pain after spinal cord injury. J Neurotrauma 29:898–904

    Article  PubMed  PubMed Central  Google Scholar 

  • Tian R et al (2016) Rutin ameliorates diabetic neuropathy by lowering plasma glucose and decreasing oxidative stress via Nrf2 signaling pathway in rats. Eur J Pharmacol 771:84–92

    Article  PubMed  CAS  Google Scholar 

  • van Dam PS (2002) Oxidative stress and diabetic neuropathy: pathophysiological mechanisms and treatment perspectives. Diabetes Met Res Rev 18:176–184

    Article  Google Scholar 

  • Wang H, Joseph JA (1999) Quantifying cellular oxidative stress by dichlorofluorescein assay using microplate reader. Free Rad Biol Med 27:612–616

    Article  PubMed  CAS  Google Scholar 

  • Wang X et al (2017) Tenuigenin inhibits LPS-induced inflammatory responses in microglia via activating the Nrf2-mediated HO-1 signaling pathway. Eur J Pharmacol 809:196–202

    Article  PubMed  CAS  Google Scholar 

  • Wills ED (1966) Mechanisms of lipid peroxide formation in animal tissues. Biochem J 99:667–676

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Xu X, Zhang D, Liao J, Wang Q, Qiu W (2016) Galanin and its receptor system promote the repair of injured aciatic nerves in diabetic rats. Neural Regen Res 11:1517–1526

    PubMed  PubMed Central  Google Scholar 

  • Yama K, Sato K, Abe N, Murao Y, Tatsunami R, Tampo Y (2015) Epalrestat increases glutathione, thioredoxin, and heme oxygenase-1 by stimulating Nrf2 pathway in endothelial cells. Redox Biol 4:87–96

    Article  PubMed  CAS  Google Scholar 

  • Yang X et al (2016) Paeoniflorin protects Schwann cells against high glucose induced oxidative injury by activating Nrf2/ARE pathway and inhibiting apoptosis. J Ethnopharmacol 185:361–369

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The present study was funded by Department of science and technology (DST), (Grant SR/WOS-A/LS-1324/2014 dated 14.05.2015), New Delhi has been gratefully acknowledged.

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Authors and Affiliations

  1. Neuropharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University, Chandigarh, 160014, India

    Ruchika Mittal & Anil Kumar

  2. National Agri-Food Biotechnology Institute (NABI), Sector-81, SAS Nagar, Mohali, 140306, Punjab, India

    Dhirendra Pratap Singh & Mahendra Bishnoi

  3. Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India

    Tapas Chandra Nag

Authors
  1. Ruchika Mittal
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  2. Anil Kumar
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  3. Dhirendra Pratap Singh
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  4. Mahendra Bishnoi
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  5. Tapas Chandra Nag
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Correspondence to Anil Kumar.

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Ruchika Mittal (nee Garg).

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Mittal, R., Kumar, A., Singh, D.P. et al. Ameliorative potential of rutin in combination with nimesulide in STZ model of diabetic neuropathy: targeting Nrf2/HO-1/NF-kB and COX signalling pathway. Inflammopharmacol 26, 755–768 (2018). https://doi.org/10.1007/s10787-017-0413-5

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  • DOI: https://doi.org/10.1007/s10787-017-0413-5

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