Skip to main content
SpringerLink
Log in

Gabapentin, a Synthetic Analogue of Gamma Aminobutyric Acid, Reverses Systemic Acute Inflammation and Oxidative Stress in Mice

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

The aim of this study was to investigate the potential anti-inflammatory and anti-oxidant effects of gabapentin (GBP) in mice. The anti-inflammatory and anti-oxidant effects were evaluated using various mediators that induce paw edema, peritonitis model, myeloperoxidase (MPO) activity, proinflammatory cytokine levels, glutathione (GSH) consumption, and malondialdehyde (MDA) production in mice. Pretreatment of mice with GBP (1 mg/kg) significantly reduced carrageenan or dextran-induced paw edema (P < 0.05) when compared to vehicle group. Adding to this, GBP (1 mg/kg) significantly inhibited paw edema induced by histamine, serotonin, bradikinin, 48/80 compound, and prostaglandin E2. In the carrageenan-induced peritonitis model, GBP significantly decreased total and differential leukocyte counts and reduced the levels of MPO activity in the plantar tissue and IL-1β and TNF-α concentrations in the peritoneal exudate. The same dose of GBP also decreased the MDA concentration and increased the levels of GSH into the peritoneal fluid. In summary, our results demonstrated that GBP exhibited anti-inflammatory activity in mice by reducing the action of inflammatory mediators, neutrophil migration and proinflammatory cytokine levels, and anti-oxidant properties by decreasing the concentration of MDA and increasing the GSH content. These observations raise the possibility that GBP could be used to improve tissue resistance to damage during inflammatory conditions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Shimoyama, M., N. Shimoyama, C.E. Inturrisi, and K.J. Elliott. 1997. Gabapentin enhances the antinociceptive effects of spinal morphine in the rat tail-flick test. Pain 72: 375–382.

    Article  PubMed  CAS  Google Scholar 

  2. Hwang, J.H., and T.L. Yaksh. 1997. Effect of subarachnoid gabapentin on tactile-evoked allodynia in a surgically induced neuropathic pain model in the rat. Reg Anesth 22: 249–256.

    Article  PubMed  CAS  Google Scholar 

  3. Backonja, M., A. Beydoun, K.R. Edwards, S.L. Schwartz, V. Fonseca, M. Hes, L. La Moreaux, and E. Garofalo. 1998. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA b280: 1831–1836.

    Article  Google Scholar 

  4. Singh, D., and D.H. Kennedy. 2003. The use of gabapentin for the treatment of postherpetic neuralgia. Clin Ther 25: 852–889.

    Article  PubMed  CAS  Google Scholar 

  5. Pöllmann, W., and W. Feneberg. 2008. Current management of pain associated with multiple sclerosis. CNS Drugs 22: 291–324.

    Article  PubMed  Google Scholar 

  6. Abdel-Salam, O.M.E., and A.A. Sleem. 2009. Study of the analgesic, anti-inflammatory, and gastric effects of gabapentin. Drug Discov Ther 3: 18–26.

    PubMed  CAS  Google Scholar 

  7. Silva, V.G., R.O. Silva, S.R. Damasceno, N.S. Carvalho, R.S. Prudêncio, K.S. Aragão, M.A. Guimarães, S.A. Campos, L.M. Véras, M. Godejohann, J.R. Leite, A.L. Barbosa, and J.V. Medeiros. 2013. Anti-inflammatory and antinociceptive activity of epiisopiloturine, an imidazole alkaloid isolated from Pilocarpus microphyllus. J Nat Prod 76: 1071–1077.

    Article  PubMed  CAS  Google Scholar 

  8. Vinegar, R., J.F. Truax, J.L. Selph, P.R. Johnston, A.L. Venable, and K.K. McKenzie. 1987. Pathway to carrageenan-induced inflammation in the hind limb of the rat. Fed Proc 46: 118–126.

    PubMed  CAS  Google Scholar 

  9. Carvalho, W.A., and L. Lemônica. 1998. Mecanismos celulares e moleculares da dor inflamatória. Rev Bras Anestesiol 48: 137–158.

    CAS  Google Scholar 

  10. Greer, C.W., I. Shomera, M.E. Goldsteinb, and W. Yaphe. 1984. Analysis of carrageenan from Hypnea musciformis by using κ- and ι-carrageenases and 13C-N.M.R. spectroscopy. Carbohydr Res 129: 189–196.

    Article  CAS  Google Scholar 

  11. Aziza, M., T. Givernaud, M. Chikhaoui-khay, and L. Bennasser. 2008. Seasonal variation of the growth, chemical composition and carrageenan extracted from Hypnea musciformis (Wulfen) Lamouroux harvested along the Atlantic coast of Morocco. Sci Res Essays 2: 509–514.

    Google Scholar 

  12. Carvalho, J.C., J.R. Teixeira, P.J. Souza, J.K. Bastos, D. dos Santos Filho, and S.J. Sarti. 1996. Preliminary studies of analgesic and anti-inflammatory properties of Caesalpinea ferrea crude extract. J Ethnopharmacol 53: 175–178.

    Article  PubMed  CAS  Google Scholar 

  13. Hajare, S.W., S. Chandra, J. Sharma, S.K. Tandan, J. Lal, and A.G. Telang. 2001. Anti-inflammatory activity of Dalbergia sissoo leaves. Fitoterapia 72: 131–139.

    Article  PubMed  CAS  Google Scholar 

  14. Srinivasan, K., S. Muruganandan, J. Lal, S. Chandra, S.K. Tandan, and V.R. Prakash. 2001. Evaluation of anti-inflammatory activity of Pongamia pinnata leaves in rats. J Ethnopharmacol 78: 151–157.

    Article  PubMed  CAS  Google Scholar 

  15. Calixto, J.B., M.M. Campos, M.F. Otuki, and A.R. Santos. 2004. Anti-inflammatory compounds of plant origin. Part II. Modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. Planta Med 70: 93–103.

    Article  PubMed  CAS  Google Scholar 

  16. Lanhers, M.C., J. Fleurentin, P. Dorfman, F. Mortier, and J.M. Pelt. 1991. Analgesic, antipyretic and anti-inflammatory properties of Euphorbia hirta. Planta Med 57: 225–231.

    Article  PubMed  CAS  Google Scholar 

  17. Mihara, M., and M. Uchiyama. 1978. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Ana Biochem 86: 271–278.

    Article  CAS  Google Scholar 

  18. Sedlak, J., and R.H. Lindsay. 1968. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem 24: 1992–2005.

    Google Scholar 

  19. Jensen, A.A., J. Mosbacher, S. Elg, K. Lingenhoehl, T. Lohmann, T.N. Johansen, B. Abrahamsen, J.P. Mattsson, A. Lehmann, B. Bettler, and H. Bräuner-Osborne. 2002. The anticonvulsant gabapentin (neurontin) does not act through gamma-aminobutyric acid-B receptors. Mol Pharmacol 6: 1377–1384.

    Article  Google Scholar 

  20. Bennett, M.I., and K.H. Simpson. 2004. Gabapentin in the treatment of neuropathic pain. Palliat Med 18: 5–11.

    Article  PubMed  Google Scholar 

  21. Abdi, S., D.H. Lee, and J.M. Chung. 1998. The anti-allodynic effects of amitriptyline, gabapentin, and lidocaine in a rat model of neuropathic pain. Anesth Analg 87: 1360–1366.

    PubMed  CAS  Google Scholar 

  22. Yasuda, T., S. Miki, N. Yoshinaga, and E. Senba. 2005. Effects of amitriptyline and gabapentin on bilateral hyperalgesia observed in an animal model of unilateral axotomy. Pain 115: 161–170.

    Article  PubMed  CAS  Google Scholar 

  23. Shimoyama, N., M. Shimoyama, A.M. Davis, C.E. Inturrisi, and K.J. Elliott. 1997. Spinal gabapentin is antinociceptive in the rat formalin test. Neurosci Lett 222: 65–67.

    Article  PubMed  CAS  Google Scholar 

  24. Hunter, J.C., K.R. Gogas, L.R. Hedley, L.O. Jacobson, L. Kassotakis, J. Thompson, and D.J. Fontana. 1997. The effect of novel anti-epileptic drugs in rat experimental models of acute and chronic pain. Eur J Pharmacol 324: 153–160.

    Article  PubMed  CAS  Google Scholar 

  25. Vinegar, R., W. Schreiber, and R. Hugo. 1969. Biphasic development of carrageenin edema in rats. J Pharmacol Exp Ther 166: 96–103.

    PubMed  CAS  Google Scholar 

  26. de Brito, T.V., R.S. Prudêncio, A.B.. Sales, F. Vieira Jr., S.J. Candeira, Á.X. Franco, K.S. Aragão, R.A. Ribeiro, Ponte de Souza MH, L.S. Chaves, A.L. Freitas, J.V. Medeiros, and A.L.R. Barbosa. 2013. Anti-inflammatory effect of a sulphated polysaccharide fraction extracted from the red algae Hypnea musciformis via the suppression of neutrophil migration by the nitric oxide signalling pathway. J Pharm Pharmacol 65: 724–733.

  27. Dawson, J., A.D. Sedgwick, J.C.W. Edwards, and P. Lees. 1991. A comparative study of the cellular, exudative and histological responses to carrageenan, dextran and zymosan in the mouse. Inter J Tissue Reac 13–14: 171–185.

    Google Scholar 

  28. Cragg, G.M., D.J. Newman, and K.M. Snader. 1997. Natural products in drug discovery and development. J Nat Prod 60: 52–60.

    Article  PubMed  CAS  Google Scholar 

  29. De Smet, P.A. 2007. The role of plant-derived drugs and herbal medicines in healthcare. Drugs 54: 801–840.

    Article  Google Scholar 

  30. Rowley, D.A., and E.P. Benditt. 1956. 5-hydroxytryptamine and histamine as mediators of the vascular injury produced by agents which damage mast cells in rats. J Exp Med 103: 399–415.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Kulkarni, S.K., A.K. Mehta, and J. Kunchandy. 1986. Anti-inflammatory actions of clonidine, guanfacine and B-HT 920 against various inflammagen-induced acute paw oedema in rats. Arch Int Pharmacodyn Ther 279: 324–334.

    PubMed  CAS  Google Scholar 

  32. Seibert, K., Y. Zhang, K. Leahy, S. Hauser, J. Masferrer, W. Perkins, L. Lee, and P. Isakson. 1994. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci 91: 12013–12017.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Lago, J., A. Alfonso, M.R. Vieytes, and L.M. Botana. 2001. Ouabain-induced enhancement of rat mast cells response. Modulation by protein phosphorylation and intracellular pH. Cell Signal 13: 515–524.

    Article  PubMed  CAS  Google Scholar 

  34. Okazaki, T., V.S. Ilea, A. Okazaki, K. Wicher, R.E. Reisman, and C.E. Arbesman. 1976. Inhibition of antigen-induced histamine release by ouabain. J Allergy Clin Immunol 57: 454–462.

    Article  PubMed  CAS  Google Scholar 

  35. Senol, M., I.H. Ozerol, A.V. Patel, and D.P. Skoner. 2007. The effect of Na+-K+ATPase inhibition by ouabain on histamine release from human cutaneous mast cells. Mol Cell Biochem 294: 25–29.

    Article  PubMed  CAS  Google Scholar 

  36. Ajuebor, M.N., A. Singh, and J.L. Wallace. 2000. Cyclooxygenase-2-derived prostaglandin D2 is an early anti-inflammatory signal in experimental colitis. J Physiol Gastrointest Liver Physiol 279: 238–244.

    Google Scholar 

  37. Souza, G.E., F.Q. Cunha, R. Mello, and S.H. Ferreira. 1988. Neutrophil migration induced by inflammatory stimuli is reduced by macrophage depletion. Agents Actions 24: 377–380.

    Article  PubMed  CAS  Google Scholar 

  38. Klebanoff, S.J. 1999. Myeloperoxidase. Proc. Assoc. Am. Physicians 111: 383–389.

    PubMed  CAS  Google Scholar 

  39. Gupta, M., U.K. Mazumdar, T. Sivakumar, M.L. Vamsi, S.S. Karki, R. Sambathkumar, and L. Manikandan. 2003. Evaluation of anti-inflammatory activity of chloroform extract of Bryonia laciniosa in experimental animal models. Biol Pharm Bull 26: 1342–1344.

    Article  PubMed  CAS  Google Scholar 

  40. Chaves, L.S., L.A. Nicolau, R.O. Silva, F.C. Barros, A.L. Freitas, K.S. Aragão, R.A. Ribeiro, M.H. Souza, A.L. Barbosa, and J.V. Medeiros. 2013. Antiinflammatory and antinociceptive effects in mice of a sulfated polysaccharide fraction extracted from the marine red algae Gracilaria caudate. Immunopharmacol Immunotoxicol 35: 93–100.

    Article  CAS  Google Scholar 

  41. Metcalfe, D.D. 2008. Mast cells and mastocytosis. Blood 15: 946–956.

    Article  Google Scholar 

  42. Sutbeyaz, Y., B. Yakan, H. Ozdemir, M. Karasen, F. Doner, and I. Kufrevioglu. 1996. Effect of SC-41930, a potent selective leukotriene B4 receptor antagonist, in the guinea pig model of middle ear inflammation. Ann Otol Rhinol Laryngol 105: 476–480.

    PubMed  CAS  Google Scholar 

  43. Josse, C., J.R. Boelaert, M. Best-Belpomme, and J. Piette. 2001. Importance of post-transcriptional regulation of chemokine genes by oxidative stress. Biochem J 360: 321–333.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  44. Cuzzocrea, S., D.P. Riley, A.P. Caputi, and D. Salvemini. 2001. Antioxidant therapy: a new pharmacological approach in shock, inflammation and ischemia/reperfusion injury. Pharmacol Rev 53: 135–159.

    PubMed  CAS  Google Scholar 

  45. Amirshahrokhi, K., S. Bohlooli, and M.M. Chinifroush. 2011. The effect of methylsulfonylmethane on the experimental colitis in the rat. T Appl Pharmacol 253: 197–202.

    Article  CAS  Google Scholar 

  46. Pacher, P., J.S. Beckman, and L. Liaudet. 2007. Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87: 315–424.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge the National Council of Technological and Scientific Development, CNPq, (Brazil) and the Research Foundation for the State of Piauí-Brazil (FAPEPI) for financially supporting this work.

Conflict of Interest

The authors report no conflict of interest.

Author information

Authors and Affiliations

  1. LAFFEX—Laboratory of Experimental Physiopharmacology, Biotechnology and Biodiversity Center Research (BIOTEC), Federal University of Piauí, Parnaiba-PI, 64049-550, Brazil

    Jordana Maia Dias, Tarcisio Vieira de Brito, Diva de Aguiar Magalhães, Pammela Weryka da Silva Santos, Jalles Arruda Batista, Eulina Gabriela do Nascimento Dias, Heliana de Barros Fernandes, Jand-Venes R. Medeiros & André Luiz R. Barbosa

  2. LAFICA—Laboratory of Pharmacology of Inflammation and Cancer, Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil

    Samara Rodrigues Bonfim Damasceno, Renan O. Silva, Karoline S. Aragão & Marcellus H. L. P. Souza

Authors
  1. Jordana Maia Dias
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tarcisio Vieira de Brito
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Diva de Aguiar Magalhães
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pammela Weryka da Silva Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jalles Arruda Batista
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eulina Gabriela do Nascimento Dias
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Heliana de Barros Fernandes
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Samara Rodrigues Bonfim Damasceno
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Renan O. Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Karoline S. Aragão
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Marcellus H. L. P. Souza
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jand-Venes R. Medeiros
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. André Luiz R. Barbosa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to André Luiz R. Barbosa.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dias, J.M., de Brito, T.V., de Aguiar Magalhães, D. et al. Gabapentin, a Synthetic Analogue of Gamma Aminobutyric Acid, Reverses Systemic Acute Inflammation and Oxidative Stress in Mice. Inflammation 37, 1826–1836 (2014). https://doi.org/10.1007/s10753-014-9913-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-014-9913-2

KEY WORDS

Search

Navigation