Kaempferol Attenuates the Development of Diabetic Neuropathic Pain in Mice: Possible Anti-Inflammatory and Anti-Oxidant Mechanisms

Authors

  • Osama M. Abo-Salem College of Applied Medical Sciences - Laboratory Sciences and Clinical Technology, Taif University, Taif +966

DOI:

https://doi.org/10.3889/oamjms.2014.073

Keywords:

Kaempferol, Diabetic neuropathy, cytokines, Oxidative, stress

Abstract

BACKGROUND: Diabetic neuropathic pain (DNP) is one of the most difficult types of pain to treat.  Many studies emphasized on the role of microglial cells, oxidative stress (OS) and inflammatory cytokines (IC) in the development of diabetic neuropathy (DN).

AIM: Present study was designed to evaluate the effect of kaempferol in attenuation of DN in mice. 

METHODS: Diabetes was induced in mice by i.p. injection of a single dose of streptozotocin (STZ) (200 mg/kg). Cold allodynia, thermal hyperalgesia and chemical hyperalgesia were assessed, as well as markers of inflammation and OS.

RESULTS: Diabetic mice (DM) showed an increased pain sensation, IC and OS accompanied with reduced body weigh gain. Treatment of DM with kaempferol (25, 50 and 100 mg/kg/day/orally) attenuated the development of DN and reduced pain sensation. Moreover, it reduced interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), lipid peroxidation and nitrite, concomitant with the improvement of antioxidant defense and body weight gain. In contrast, kaempferol (100 mg/kg) had no effects on the behavioral and biochemical parameters. Our results strongly suggest that activated microglia, IC and OS are involved in the development of DN.

CONCLUSIONS: Kaempferol attenuates the development of DNP in mice probably by inhibition of neuroimmune activation of microglia and, partly mediated by reducing IC and OS.

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References

Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005; 54: 1615–1625. DOI: https://doi.org/10.2337/diabetes.54.6.1615

Stevens MJ. Effects of DL-α-lipoic acid on peripheral nerve conduction, blood flow, energy metabolism, and oxidative stress in experimental diabetic neuropathy. Diabetes. 2000; 49:1006–1015. DOI: https://doi.org/10.2337/diabetes.49.6.1006

Quan Y et al. High glucose stimulates GRO secretion from rat microglia via ROS, PKC, and NF-kappaB pathways. J Neurosci Res. 2007; 85: 3150–3159. DOI: https://doi.org/10.1002/jnr.21421

Kellogg AP, Pop-Busui R. Peripheral nerve dysfunction in experimental diabetes is mediated by cyclooxygenase-2 and oxidative stress. Antioxid Redox Signal. 2005; 7: 1521–9. DOI: https://doi.org/10.1089/ars.2005.7.1521

Drel VR et al. A peroxynitrite decomposition catalyst counteracts sensory neuropathy in streptozotocin-diabetic mice. Eur J Pharmacol. 2007; 569: 48–58. DOI: https://doi.org/10.1016/j.ejphar.2007.05.055

Conti G et al. Macrophage infiltration and death in the nerve during the early phases of experimental diabetic neuropathy: a process concomitantwith endoneurial induction of IL-1beta and p75NTR. J Neurol Sci. 2002; 195: 35-40. DOI: https://doi.org/10.1016/S0022-510X(01)00684-0

Skundric DS, Lisak RP. Role of neuropoietic cytokines in development and progression of diabetic polyneuropathy: from glucose metabolism to neurodegeneration. Exp Diabesity Res. 2003; 4: 303–312. DOI: https://doi.org/10.1155/EDR.2003.303

Raghavendra V et al. Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J Pharmacol Exp Ther. 2003; 306: 624–630. DOI: https://doi.org/10.1124/jpet.103.052407

Daulhac L et al. Diabetes-induced mechanical hyperalgesia involves spinal mitogen-activated protein kinase activation in neurons and microglia via N-methyl-D-aspartatedependent mechanisms. Mol Pharmacol. 2006; 70: 1246–1254. DOI: https://doi.org/10.1124/mol.106.025478

Krady JK et al. Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in rodent model of diabetic retinopathy. Diabetes. 2005; 54: 1559–1565. DOI: https://doi.org/10.2337/diabetes.54.5.1559

Luo Y et al. Neuronal and glial response in the rat hypothalamus neurohypophysis complex with streptozotocin-induced diabetes. Brain Res. 2002; 925: 42–54. DOI: https://doi.org/10.1016/S0006-8993(01)03258-9

Li J et al. Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes. Proc Natl Acad Sci. 2005; 102: 9936–9941. DOI: https://doi.org/10.1073/pnas.0502552102

Candelario-Jalil E et al. Resveratrol potently reduces prostaglandin E2 production and free radical formation in lipopolysaccharide-activated primary rat microglia. J Neuroinflammation. 2007; 4: 25-31. DOI: https://doi.org/10.1186/1742-2094-4-25

Ledeboer A et al. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain. 2005; 115: 71–83. DOI: https://doi.org/10.1016/j.pain.2005.02.009

Tikka TM, Koistinaho JE. Minocycline provides neuroprotection against Nmethyl-D-aspartate neurotoxicity by inhibiting microglia. J Immunol. 2001; 166: 7527–7533. DOI: https://doi.org/10.4049/jimmunol.166.12.7527

Wong MC et al. Effects of treatments for symptoms of painful diabetic neuropathy: systematic review. BMJ. 2007; 335: 87-94. DOI: https://doi.org/10.1136/bmj.39213.565972.AE

Calderon-Montano JM et al. Areview on the dietary flavonoid kaempferol. Mini Rev Med Chem. 2011; 11(4): 298-344. DOI: https://doi.org/10.2174/138955711795305335

Anjaneyulu M, Chopra K. Fluoxetine attenuates thermal hyperalgesia through 5-HT1/2 receptors in streptozotocin-induced diabetic mice. Eur J Pharmacol. 2004; 497: 285–92. DOI: https://doi.org/10.1016/j.ejphar.2004.06.063

Li S, Pu XP. Neuroprotective effect of kaempferol against a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease. Biol Pharm Bull. 2011; 34(8): 1291-6. DOI: https://doi.org/10.1248/bpb.34.1291

Zhang Y, Liu D. Flavonol kaempferol improves chronic hyperglycemia-impaired pancreatic beta-cell viability and insulin secretory function. Eur J Pharmacol. 2011; 670(1): 325-32. DOI: https://doi.org/10.1016/j.ejphar.2011.08.011

Parveen Z et al. Antiinflammatory and analgesic activities of Thesium chinense Turcz extracts and its major flavonoids, kaempferol and kaempferol-3-O-glucoside. Yakugaku Zasshi. 2007; 127(8): 1275-9. DOI: https://doi.org/10.1248/yakushi.127.1275

De Melo GO et al. Antinociceptive and anti-inflammatory kaempferol glycosides from Sedum dendroideum. J Ethnopharmacol. 2009; 124(2): 228-32. DOI: https://doi.org/10.1016/j.jep.2009.04.024

Padi SSV, Kulkarni SK. Differential effects of naproxen and rofecoxib on the development of hypersensitivity following nerve injury in rats. Pharmacol Biochem Behav. 2004; 79: 349–358. DOI: https://doi.org/10.1016/j.pbb.2004.08.005

Calcutt NA et al. Tactile allodynia and formalin hyperalgesia in streptozotocin-diabetic rats: effects of insulin, aldose reductase inhibition and lidocaine. Pain. 1996; 68: 293–9. DOI: https://doi.org/10.1016/S0304-3959(96)03201-0

Padi SSV et al. Pharmacological profile of parecoxib: a novel, potent injectable selective cyclooxygenase-2 inhibitor. Eur J Pharmacol. 2004; 491: 69–76. DOI: https://doi.org/10.1016/j.ejphar.2004.03.013

Abo-Salem OM et al. Antinociceptive effects of novel A2B adenosine receptor antagonists. J Pharmacol Exp Ther. 2004; 308: 358–366. DOI: https://doi.org/10.1124/jpet.103.056036

Bilkei-Gorzo A et al. Adenosine receptor subtype-selective antagonists in inflammation and hyperalgesia. Naunyn-Schmiedeberg_s Arch Pharmacol. 2008; 377: 65–76. DOI: https://doi.org/10.1007/s00210-007-0252-9

Barham D, Trinder P. An improved colour reagent for the determination of blood glucose by the oxidase system. Analyst. 1972; 97: 142-149. DOI: https://doi.org/10.1039/an9729700142

Abrams JS. Immunoenzymatic assay of cytokines using NIP-labeled antibodies. In: Current Protocols in Immunology, (ed). J. Coligan, A. Kruisbeck, D. Margulies, E. Shevach and W. Strober. John Wiley & Sons: New York, 1995: 620-680.

Hortelano S et al. Nitric oxide is released resulting in regenerating liver after partial hepatectomy. Hepatol. 1995; 21: 776-786. DOI: https://doi.org/10.1002/hep.1840210327

Draper HH, Hadley M. Methods in Enzymology, Academic Press: New York, 1990: 421-455. DOI: https://doi.org/10.1016/0076-6879(90)86135-I

Ellman MA. Spectrophotometric method for determination of reduced glutathione in tissues. Analyt Biochem. 1959; 74: 214-226. DOI: https://doi.org/10.1016/0003-2697(76)90326-2

Yagihashi S et al. Pathology and pathogenetic mechanisms of diabetic neuropathy: correlation with clinical signs and symptoms. Diabetes Res Clin Pract. 2007; 77: 184–189. DOI: https://doi.org/10.1016/j.diabres.2007.01.054

Abo-Salem OM et al. Experimental diabetic nephropathy can be prevented by propolis: effect on metabolic disturbances And renal oxidative parameters. Pak J Pharm Sci. 2009; 22(2): 205-210.

Faux SP, Howden PJ. Possible role of lipid peroxidation in the induction of NF-kappa B and AP-1 in RFL-6 cells by crocidolite asbestos: evidence following protection by vitamin E. Environ Health Perspect. 1997; 105: 1127–30. DOI: https://doi.org/10.2307/3433520

Sharma S et al. Effect of insulin and its combination with resveratrol or curcumin in attenuation of diabetic neuropathic pain: participation of nitric oxide and TNFalpha. Phytother Res. 2007; 21: 278–83. DOI: https://doi.org/10.1002/ptr.2070

Liang YC et al. Suppression of inducible cyclooxygenase and inducible nitric oxide synthase by apigenin and related flavonoids in mouse macrophages. Carcinogenesis. 1999; 20: 1945-1952. DOI: https://doi.org/10.1093/carcin/20.10.1945

Lagoa R et al. Kaempferol protects against rat striatal degeneration induced by 3-nitropropionic acid. J Neurochem. 2009; 111(2): 473-87. DOI: https://doi.org/10.1111/j.1471-4159.2009.06331.x

Park SE et al. Kaempferol acts through mitogen-activated protein kinases and protein kinase B/AKT to elicit protection in a model of neuroinflammation in BV2 microglial cells. Br J Pharmacol. 2011; 164(3): 1008-25. DOI: https://doi.org/10.1111/j.1476-5381.2011.01389.x

Bal-Price A, Brown GC. Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicity. J Neurosci. 2001; 21: 6480–6491. DOI: https://doi.org/10.1523/JNEUROSCI.21-17-06480.2001

Thacker MA et al. Pathophysiology of peripheral neuropathic pain: Immune cells and molecules. Anesth Analg. 2007; 105: 838–847. DOI: https://doi.org/10.1213/01.ane.0000275190.42912.37

Kowalski J et al. Effect of kaempferol on the production and gene expression of monocyte chemoattractant protein-1 in J774.2 macrophages. Pharmacol Rep. 2005; 57: 107–112.

Chen X et al. Kaempferol regulates MAPKs and NF-κB signaling pathways to attenuate LPS-induced acute lung injury in mice. Int Immunopharmacol. 2012; 14(2): 209-16. DOI: https://doi.org/10.1016/j.intimp.2012.07.007

Narita M et al. Direct evidence for spinal cord microglia in the development of a neuropathic pain-like state in mice. J Neurochem. 2006; 97: 1337–1348. DOI: https://doi.org/10.1111/j.1471-4159.2006.03808.x

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Published

2014-09-15

How to Cite

1.
Abo-Salem OM. Kaempferol Attenuates the Development of Diabetic Neuropathic Pain in Mice: Possible Anti-Inflammatory and Anti-Oxidant Mechanisms. Open Access Maced J Med Sci [Internet]. 2014 Sep. 15 [cited 2024 May 5];2(3):424-30. Available from: https://oamjms.eu/index.php/mjms/article/view/oamjms.2014.073

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Section

A - Basic Science