title: Vinpocetine reduces carrageenan-induced inflammatory hyperalgesia in mice by inhibiting oxidative stress, cytokine production and NF-κB activation in the paw and spinal cord.
abstract: Vinpocetine is a safe nootropic agent used for neurological and cerebrovascular diseases. The anti-inflammatory activity of vinpocetine has been shown in cell based assays and animal models, leading to suggestions as to its utility in analgesia. However, the mechanisms regarding its efficacy in inflammatory pain treatment are still not completely understood. Herein, the analgesic effect of vinpocetine and its anti-inflammatory and antioxidant mechanisms were addressed in murine inflammatory pain models. Firstly, we investigated the protective effects of vinpocetine in overt pain-like behavior induced by acetic acid, phenyl-p-benzoquinone (PBQ) and formalin. The intraplantar injection of carrageenan was then used to induce inflammatory hyperalgesia. Mechanical and thermal hyperalgesia were evaluated using the electronic von Frey and the hot plate tests, respectively, with neutrophil recruitment to the paw assessed by a myeloperoxidase activity assay. A number of factors were assessed, both peripherally and in the spinal cord, including: antioxidant capacity, reduced glutathione (GSH) levels, superoxide anion, tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) levels, as well as nuclear factor kappa B (NF-κB) activation. Vinpocetine inhibited the overt pain-like behavior induced by acetic acid, PBQ and formalin (at both phases), as well as the carrageenan-induced mechanical and thermal hyperalgesia and associated neutrophil recruitment. Both peripherally and in the spinal cord, vinpocetine also inhibited: antioxidant capacity and GSH depletion; increased superoxide anion; IL-1β and TNF-α levels; and NF-κB activation. As such, vinpocetine significantly reduces inflammatory pain by targeting oxidative stress, cytokine production and NF-κB activation at both peripheral and spinal cord levels.
authors.affiliation: Departamento de Ciências Patológicas, Universidade Estadual de Londrina, Londrina, Paraná, Brasil.
authors.forename: Kenji W
authors.initials: KW
authors.lastname: Ruiz-Miyazawa
authors.affiliation: Departamento de Ciências Patológicas, Universidade Estadual de Londrina, Londrina, Paraná, Brasil.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Zarpelon
authors.affiliation: Departamento de Ciências Patológicas, Universidade Estadual de Londrina, Londrina, Paraná, Brasil.
authors.forename: Felipe A
authors.initials: FA
authors.lastname: Pinho-Ribeiro
authors.affiliation: Departamento de Ciências Farmacêuticas, Universidade Estadual de Londrina Londrina, Hospital Universitário, Londrina, Paraná, Brasil.
authors.forename: Gabriela F
authors.initials: GF
authors.lastname: Pavão-de-Souza
authors.affiliation: Departamento de Ciências Farmacêuticas, Universidade Estadual de Londrina Londrina, Hospital Universitário, Londrina, Paraná, Brasil.
authors.forename: Rubia
authors.initials: R
authors.lastname: Casagrande
authors.affiliation: Departamento de Ciências Patológicas, Universidade Estadual de Londrina, Londrina, Paraná, Brasil.
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
mesh_terms: D000818:Animals; D002351:Carrageenan / Q000633:toxicity; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005121:Extremities / Q000503:physiopathology; D005978:Glutathione / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D013481:Superoxides / Q000378:metabolism; D014748:Vinca Alkaloids / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D018696:Neuroprotective Agents; D014748:Vinca Alkaloids; D013481:Superoxides; C013983:vinpocetine; D002351:Carrageenan; D005978:Glutathione
references.citation: J Leukoc Biol. 2008 Apr;83(4):824-32
references.pmid: 18203872
references.citation: Br J Pharmacol. 1992 Nov;107(3):660-4
references.pmid: 1472964
references.citation: PLoS One. 2014 Aug 25;9(8):e104939
references.pmid: 25153081
references.citation: J Chem Neuroanat. 2004 Mar;27(1):23-32
references.pmid: 15036360
references.citation: J Neurosci. 2008 Dec 24;28(52):14062-73
references.pmid: 19109489
references.citation: Respir Med. 2009 Jul;103(7):975-94
references.pmid: 19372037
references.citation: J Pharmacol Exp Ther. 2004 Jun;309(3):869-78
references.pmid: 14988418
references.citation: J Biol Chem. 2008 Apr 18;283(16):10550-8
references.pmid: 18252714
references.citation: Arzneimittelforschung. 1992 Jul;42(7):914-7
references.pmid: 1418055
references.citation: J Leukoc Biol. 2010 May;87(5):805-13
references.pmid: 20110444
references.citation: J Am Geriatr Soc. 1987 May;35(5):425-30
references.pmid: 3553281
references.citation: Eur J Pharmacol. 2008 Jul 7;588(2-3):207-12
references.pmid: 18511039
references.citation: Pharmacol Rep. 2006 Sep-Oct;58(5):680-91
references.pmid: 17085860
references.citation: Acta Neurol Scand. 2002 Dec;106(6):325-32
references.pmid: 12460136
references.citation: Trends Immunol. 2010 May;31(5):184-90
references.pmid: 20399709
references.citation: J Neurosci. 2006 Jan 4;26(1):246-55
references.pmid: 16399694
references.citation: Neurosci Lett. 2014 Apr 30;566:247-51
references.pmid: 24598438
references.citation: J Neurochem. 2013 Jan;124(2):233-40
references.pmid: 23121080
references.citation: J Pharmacol Exp Ther. 2003 Aug;306(2):498-504
references.pmid: 12730276
references.citation: Pain. 2013 Oct;154(10):2207-15
references.pmid: 23831864
references.citation: Pharmacol Ther. 2006 Oct;112(1):116-38
references.pmid: 16730375
references.citation: Biochem J. 2014 Oct 1;463(1):75-82
references.pmid: 24995813
references.citation: Biochem Biophys Res Commun. 2013 May 10;434(3):439-43
references.pmid: 23583194
references.citation: Neurochem Res. 2011 Jun;36(6):1062-72
references.pmid: 21448596
references.citation: Nat Immunol. 2001 Aug;2(8):675-80
references.pmid: 11477402
references.citation: PLoS One. 2014 Mar 03;9(3):e90013
references.pmid: 24595131
references.citation: Pharmacol Biochem Behav. 2013 Apr;105:183-92
references.pmid: 23474372
references.citation: Pain. 1977 Dec;4(2):161-74
references.pmid: 564014
references.citation: Biochim Biophys Acta. 2010 Oct-Dec;1799(10-12):775-87
references.pmid: 20493977
references.citation: Clin Exp Immunol. 2008 Sep;153(3):420-8
references.pmid: 18647324
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1755-60
references.pmid: 15665080
references.citation: J Nat Prod. 2009 Nov;72(11):1975-9
references.pmid: 19899776
references.citation: Proc Natl Acad Sci U S A. 2013 Jul 2;110(27):11193-8
references.pmid: 23776243
references.citation: J Nat Prod. 2013 Jun 28;76(6):1141-9
references.pmid: 23742617
references.citation: Am J Manag Care. 2007 Dec;13 Suppl 9:S218-23
references.pmid: 18095785
references.citation: J Photochem Photobiol B. 2013 Oct 5;127:153-60
references.pmid: 24041853
references.citation: Neuropharmacology. 2007 Dec;53(7):854-62
references.pmid: 17904592
references.citation: Pharmacol Rep. 2007 May-Jun;59(3):247-58
references.pmid: 17652824
references.citation: Cancer Cell. 2004 Sep;6(3):203-8
references.pmid: 15380510
references.citation: Ann Anat. 2008;190(2):140-5
references.pmid: 18413267
references.citation: J Pharmacol Exp Ther. 1989 Sep;250(3):1132-40
references.pmid: 2778712
references.citation: Neurochem Int. 2005 Jun;46(7):533-40
references.pmid: 15843047
references.citation: FEBS J. 2007 Sep;274(18):4812-24
references.pmid: 17697115
references.citation: Br J Pharmacol. 2013 Aug;169(7):1525-36
references.pmid: 23849041
references.citation: Neurosci Lett. 1993 Oct 1;160(2):193-6
references.pmid: 8247353
references.citation: Mult Scler. 2000 Feb;6(1):56-8
references.pmid: 10694847
references.citation: Exp Eye Res. 2014 Oct;127:49-58
references.pmid: 25041941
references.citation: Am J Respir Cell Mol Biol. 2013 Aug;49(2):288-95
references.pmid: 23590300
references.citation: Neuron Glia Biol. 2011 May;7(2-4):187-97
references.pmid: 22874716
references.citation: Proc Natl Acad Sci U S A. 2010 May 25;107(21):9795-800
references.pmid: 20448200
references.citation: Physiol Behav. 2014 Apr 10;128:277-87
references.pmid: 24518865
references.citation: Biomed Res Int. 2013;2013:627046
references.pmid: 24288682
references.citation: Ann N Y Acad Sci. 2005 Nov;1056:218-33
references.pmid: 16387690
references.citation: Eur J Pharmacol. 1995 Feb 6;273(3):303-6
references.pmid: 7737339
references.citation: Zh Nevropatol Psikhiatr Im S S Korsakova. 1991;91(8):21-2
references.pmid: 1661506
references.citation: Neuron. 2014 Apr 2;82(1):47-54
references.pmid: 24698267
references.citation: J Immunol. 2000 Jan 15;164(2):1037-45
references.pmid: 10623854
references.citation: Ann N Y Acad Sci. 1996 Oct 31;796:104-12
references.pmid: 8906217
references.citation: Nat Rev Neurosci. 2006 Oct;7(10):797-809
references.pmid: 16988655
references.citation: Blood. 1982 Sep;60(3):618-22
references.pmid: 6286012
references.citation: Eur J Pharm Biopharm. 2011 Jan;77(1):43-55
references.pmid: 21056658
references.citation: Lik Sprava. 2000 Sep;(6):8-10
references.pmid: 11452930
references.citation: Eur J Pharmacol. 1992 Oct 6;221(1):171-4
references.pmid: 1333972
references.citation: J Neurochem. 2014 Sep;130(6):770-9
references.pmid: 24903676
references.citation: J Biol Chem. 1996 Oct 11;271(41):25699-706
references.pmid: 8810348
references.citation: PLoS One. 2013 Dec 09;8(12):e82509
references.pmid: 24349299
references.citation: Free Radic Biol Med. 2011 Sep 1;51(5):951-66
references.pmid: 21277369
references.citation: Eur J Nucl Med Mol Imaging. 2002 Aug;29(8):1031-8
references.pmid: 12173017
references.citation: Braz J Med Biol Res. 2004 Mar;37(3):401-7
references.pmid: 15060710
references.citation: Neurochem Res. 1999 Dec;24(12):1585-91
references.pmid: 10591410
references.citation: Biochem Pharmacol. 2001 Apr 1;61(7):877-92
references.pmid: 11274974
references.citation: Eur J Clin Pharmacol. 1985;28(5):567-71
references.pmid: 3899677
references.citation: Pain. 1987 Jul;30(1):103-14
references.pmid: 3614974
references.citation: Pain. 2005 Jan;113(1-2):185-90
references.pmid: 15621379
references.citation: Cochrane Database Syst Rev. 2003;(1):CD003119
references.pmid: 12535455
references.citation: Brain Res Bull. 2000 Oct;53(3):245-54
references.pmid: 11113577
references.citation: Epilepsy Res. 2011 Oct;96(3):257-66
references.pmid: 21737246
references.citation: Neurochem Res. 2001 Sep;26(8-9):1095-100
references.pmid: 11699936
references.citation: Zh Nevrol Psikhiatr Im S S Korsakova. 2012;112(12 Pt 2):20-30
references.pmid: 23388602
references.citation: Nature. 1988 Aug 25;334(6184):698-700
references.pmid: 3137474
references.citation: Curr Pharm Des. 2002;8(14):1255-96
references.pmid: 12052219
references.citation: Br J Pharmacol. 2007 Mar;150(6):727-37
references.pmid: 17310141
references.citation: Arzneimittelforschung. 1993 Sep;43(9):981-5
references.pmid: 8240463
references.citation: Pain. 2011 Mar;152(3 Suppl):S2-15
references.pmid: 20961685
references.citation: Eur J Pharmacol. 2007 Nov 14;573(1-3):221-9
references.pmid: 17669394
references.citation: J Immunol. 2007 Nov 15;179(10):6933-42
references.pmid: 17982084
references.citation: Biochim Biophys Acta. 2012 May;1822(5):815-21
references.pmid: 22200449
references.citation: Brain Res. 2001 Jan 12;888(2):275-286
references.pmid: 11150485
references.citation: Orv Hetil. 2001 Feb 25;142(8):383-9
references.pmid: 11263076