Skip to main content

Advertisement

SpringerLink
Log in

Is l-Glutathione More Effective Than l-Glutamine in Preventing Enteric Diabetic Neuropathy?

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

Diabetes and its complications appear to be multifactorial. Substances with antioxidant potential have been used to protect enteric neurons in experimental diabetes.

Aim

This study evaluated the effects of supplementation with l-glutamine and l-glutathione on enteric neurons in the jejunum in diabetic rats.

Methods

Rats at 90 days of age were distributed into six groups: normoglycemic, normoglycemic supplemented with 2 % l-glutamine, normoglycemic supplemented with 1 % l-glutathione, diabetic (D), diabetic supplemented with 2 % l-glutamine (DG), and diabetic supplemented with 1 % l-glutathione (DGT). After 120 days, the jejunums were immunohistochemically stained for HuC/D+ neuronal nitric oxide synthase (nNOS) and vasoactive intestinal polypeptide (VIP). Western blot was performed to evaluate nNOS and VIP. Submucosal and myenteric neurons were quantitatively and morphometrically analyzed.

Results

Diabetic neuropathy was observed in myenteric HuC/D, nNOS, and VIP neurons (p < 0.05). In the submucosal plexus, diabetes did not change nitrergic innervation but increased VIPergic neuronal density and body size (p < 0.05). Supplementation with l-glutathione prevented changes in HuC/D neurons in the enteric plexus (p < 0.05), showing that supplementation with l-glutathione was more effective than with l-glutamine. Myenteric nNOS neurons in the DGT group exhibited a reduced density (34.5 %) and reduced area (p < 0.05). Submucosal neurons did not exhibit changes. The increase in VIP-expressing neurons was prevented in the submucosal plexus in the DG and DGT groups (p < 0.05).

Conclusion

Supplementation with l-glutathione exerted a better neuroprotective effect than l-glutamine and may prevent the development of enteric diabetic neuropathy.

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

Similar content being viewed by others

References

  1. Furness JB. The enteric nervous system and neurogastroenterology. Nat Rev Gastroenterol Hepatol.. 2012;9:286–294.

    Article  PubMed  CAS  Google Scholar 

  2. Gershon MD. The second brain: a groundbreaking new understanding of nervous disorders of the stomach and intestine. New York, NY: Harper Collins; 1999.

    Google Scholar 

  3. Srinivasan S, Wiley JW. New insights into neural injury, repair, and adaptation in visceral afferents and the enteric nervous system. Curr Opin Gastroenterol.. 2000;16:78–82.

    Article  PubMed  CAS  Google Scholar 

  4. Rodrigues MLC, Motta MEFA. Mechanisms and factors associated with gastrointestinal symptoms in patients with diabetes mellitus. J Pediatr. 2012;88:17–24.

    Article  Google Scholar 

  5. Nezami BG, Srinivasan S. Enteric nervous system in the small intestine: pathophysiology and clinical implications. Curr Gastroenterol Rep. 2010;12:358–365.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Vincent AM, Russell JW, Low P, Feldman EL. Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr Rev. 2004;25:612–628.

    Article  PubMed  CAS  Google Scholar 

  7. Chandrasekharan B, Anitha M, Blatt R, Shahnavaz N, et al. Colonic motor dysfunction in human diabetes is associated with enteric neuronal loss and increased oxidative stress. Neurogastroenterol Motil. 2011;23:e126–e131.

    Article  CAS  Google Scholar 

  8. Sierra VAM. Manifestaciones gastrointestinales de la diabetes mellitus. Rev Col Gastroenterol.. 2006;21:39–56.

    Google Scholar 

  9. Zanoni JN, Buttow NC, Bazotte RB, Miranda-Neto MH. Evaluation of the population of NADPH-diaphorase-stained and myosin-V myenteric neurons in the ileum of chronically streptozotocin-diabetic rats treated with ascorbic acid. Auton Neurosci.. 2003;104:32–38.

    Article  PubMed  CAS  Google Scholar 

  10. Pereira RV, de Miranda-Neto MH, da Silva Souza ID, Zanoni JN. Vitamin E supplementation in rats with experimental diabetes mellitus: analysis of myosin-V and nNOS immunoreactive myenteric neurons from terminal ileum. J Mol Histol. 2008;39:595–603.

    Google Scholar 

  11. da Silva GG, Zanoni JN, Buttow NC. Neuroprotective action of Ginkgo biloba on the enteric nervous system of diabetic rats. World J Gastroenterol. 2011;17:898–905.

    Article  PubMed Central  PubMed  Google Scholar 

  12. Lopes CRP, Ferreira PEB, Zanoni JN, Alves AMP, et al. Neuroprotective effect of quercetin on the duodenum enteric nervous system of streptozotocin-induced diabetic rats. Dig Dis Sci. 2012;57:3106–3115.

    Article  PubMed  CAS  Google Scholar 

  13. Pereira RV, Tronchini EA, Tashima CM, Alves EP, et al. l-glutamine supplementation prevents myenteric neuron loss and has gliatrophic effects in the ileum of diabetic rats. Dig Dis Sci. 2011;56:3507–3516.

    Article  PubMed  CAS  Google Scholar 

  14. Zanoni JN, Tronchini EA, Moure SA, Souza ID. Effects of l-glutamine supplementation on the myenteric neurons from the duodenum and cecum of diabetic rats. Arq Gastroenterol. 2011;48:66–71.

    Article  PubMed  Google Scholar 

  15. Tashima CM, Tronchini EA, Pereira RV, Bazotte RB, Zanoni JN. Diabetic rats supplemented with l-glutamine: a study of immunoreactive myosin-V myenteric neurons and the proximal colonic mucosa. Dig Dis Sci. 2007;52:1233–1241.

    Article  PubMed  CAS  Google Scholar 

  16. Cruzat VF, Petry ER, Tirapegui J. Glutamina: aspectos bioquímicos, metabólicos, moleculares e suplementação. Rev Bras Med Esporte.. 2009;15:392–397.

    Article  Google Scholar 

  17. Ueno Y, Kizaki M, Nakagiri R, Kamiya T, et al. Dietary glutathione protects rats from diabetic nephropathy and neuropathy. J Nutr. 2002;132:897–900.

    PubMed  CAS  Google Scholar 

  18. Bergmeyer HU, Bernet E. d-Glucose determination with glucose oxidase and peroxidase. In: Methods of Enzymatic Analysis, 2nd ed. New York, NY: Verlag Chemie-Academic Press; 1974:1205–1215.

  19. Lin Z, Gao N, Hu HZ, Liu S, et al. Immunoreactivity of Hu proteins facilitates identification of myenteric neurones in guinea-pig small intestine. Neurogastroenterol Motil. 2002;14:197–204.

    Article  PubMed  CAS  Google Scholar 

  20. Wrzos HF, Cruz A, Polavarapu R, Shearer D, Ouyang A. Nitric oxide synthase (NOS) expression in the myenteric plexus of streptozotocin-diabetic rats. Dig Dis Sci. 1997;42:2106–2110.

    Article  PubMed  CAS  Google Scholar 

  21. Costa M, Buffa R, Furness JB, Solcia E. Immunohistochemical localization of polypeptides in peripheral autonomic nerves using whole mount preparations. Histochemistry. 1980;65:157–165.

    Article  PubMed  CAS  Google Scholar 

  22. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248–254.

    Article  PubMed  CAS  Google Scholar 

  23. Alves EPB, Alves AMP, Pereira RVF, Miranda-Neto MH, Zanoni JN. Immunohistochemical study of vasoactive intestinal peptide (VIP) enteric neurons in diabetic rats supplemented with l-glutamine. Nutr Neurosci.. 2010;13:43–51.

    Article  PubMed  CAS  Google Scholar 

  24. Tsai P-H, Liu J-J, Chiu W-C, Pai M-H, Yeh S-L. Effects of dietary glutamine on adhesion molecule expression and oxidative stress in mice with streptozotocin-induced type 1 diabetes. Clin Nutr.. 2011;30:124–129.

    Article  PubMed  CAS  Google Scholar 

  25. Voukali E, Shotton HR, Lincoln J. Selective responses of myenteric neurons to oxidative stress and diabetic stimuli. Neurogastroenterol Motil. 2011;23:e411–e964.

    Article  CAS  Google Scholar 

  26. Tomlinson DR, Gardiner NJ. Glucose neurotoxicity. Nat Rev Neurosci. 2008;9:36–45.

    Article  PubMed  CAS  Google Scholar 

  27. Brownlee M. The pathobiology of diabetic complications a unifying mechanism. Diabetes. 2005;54:1615–1625.

    Article  PubMed  CAS  Google Scholar 

  28. Zanoni JN, Hernandes L, Bazotte RB, Miranda Neto MH. Terminal ileum submucous plexus: study of the VIP-ergic neurons of diabetic rats treated with ascorbic acid. Arq Neuropsiquiatr. 2002;60:32–37.

    Article  PubMed  Google Scholar 

  29. Chung SSM, Ho ECM, Lam KSL, Chung SK. Contribution of polyol pathway to diabetes-induced oxidative stress. J Am Soc Nephrol. 2003;14:S233–S236.

    Article  PubMed  CAS  Google Scholar 

  30. Shotton HR, Lincoln J. Diabetes only affects nitric oxide synthase-containing myenteric neurons that do not contain heme oxygenase 2. Brain Res. 2006;1068:248–256.

    Article  PubMed  CAS  Google Scholar 

  31. Fregonesi CE, Molinari SL, Alves AM, Defani MA, et al. Morphoquantitative aspects of nitrergic myoenteric neurons from the stomach of diabetic rats supplemented with acetyl-l-carnitine. Anat Histol Embryol. 2005;34:93–97.

    Article  PubMed  CAS  Google Scholar 

  32. de Mello ST, de Miranda Neto MH, Zanoni JN, Furlan MM. Effects of insulin treatment on HuC/HuD, NADH diaphorase, and nNOS-positive myoenteric neurons of the duodenum of adult rats with acute diabetes. Dig Dis Sci. 2009;54:731–737.

    Article  PubMed  CAS  Google Scholar 

  33. Chandrasekharan B, Srinivasan S. Diabetes and the enteric nervous system. Neurogastroenterol Motil. 2007;19:951–960.

    PubMed Central  PubMed  CAS  Google Scholar 

  34. Wiley JW. The many faces of nitric oxide: cytotoxic, cytoprotective or both. Neurogastroenterol Motil. 2007;19:541–544.

    Article  PubMed  CAS  Google Scholar 

  35. Rivera LR, Poole DP, Thacker M, Furness JB. The involvement of nitric oxide synthase neurons in enteric neuropathies. Neurogastroenterol Motil. 2011;23:980–988.

    Article  PubMed  CAS  Google Scholar 

  36. Espey MG, Miranda KM, Thomas DD, Xavier S, et al. A chemical perspective on the interplay between NO, reactive oxygen species, and reactive nitrogen oxide species. Ann NY Acad Sci.. 2002;962:195–206.

    Article  PubMed  CAS  Google Scholar 

  37. Lin Z, Sandgren K, Ekblad E. Increased expression of nitric oxide synthase in cultured neurons from adult rat colonic submucous ganglia. Auton Neurosci.. 2004;114:29–38.

    Article  PubMed  CAS  Google Scholar 

  38. Vacas E, Bajo AM, Schally AV, Sánchez-Chapado M, et al. Antioxidant activity of vasoactive intestinal peptide in HK2 human renal cells. Peptides. 2012;38:275–281.

    Article  PubMed  CAS  Google Scholar 

  39. See NA, Epstein ML, Dahl JL, Bass P. The myenteric plexus regulates cell growth in rat jejunum. J Auton Nerv Sys.. 1990;31:219–229.

    Article  CAS  Google Scholar 

  40. Rahimi R, Nikfar S, Larijani B, Abdollahi M. A review on the role of antioxidants in the management of diabetes and its complications. Biomed Pharmacother. 2005;59:365–373.

    Article  PubMed  CAS  Google Scholar 

  41. Jordão AA Jr, Chiarello PG, Bernardes MSM, Vannucchi H. Peroxidação lipídica e etanol: papel da glutationa reduzida e da vitamina E. Medicina.. 1998;32:434–449.

    Google Scholar 

  42. Daniel EE, Posey-Daniel V. Neuromuscular structures in opossum esophagus: role of interstitial cells of Cajal. Am J Physiol. 1984;246:G305–G315.

    PubMed  CAS  Google Scholar 

  43. Choi KM, Gibbons SJ, Roeder JL, Lurken MS, et al. Regulation of interstitial cells of Cajal in the mouse gastric body by neuronal nitric oxide. Neurogastroenterol Motil. 2007;19:585–595.

    Article  PubMed  CAS  Google Scholar 

  44. Li ZS, Young HM, Furness JB. Do vasoactive intestinal peptide (VIP)-and nitric oxide synthase-immunoreactive terminals synapse exclusively with VIP cell bodies in the submucous plexus of the guinea-pig ileum? Cell Tissue Res. 1995;281:485–491.

    Article  PubMed  CAS  Google Scholar 

  45. Chino Y, Fujimura M, Kitahama K, Fujimiya M. Colocalization of NO and VIP in neurons of the submucous plexus in the rat intestine. Peptides. 2002;23:2245–2250.

    Article  PubMed  CAS  Google Scholar 

  46. Mourad FH, Barada KA, Abdel-Malak N, Rached NAB, et al. Interplay between nitric oxide and vasoactive intestinal polypeptide in inducing fluid secretion in rat jejunum. J Physiol. 2003;550:863–871.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  47. Said SI, Berisha HI, Pakbaz H. N-methyl-d-aspartate receptors outside the central nervous system: activation causes acute lung injury that is mediated by nitric oxide synthesis and prevented by vasoactive intestinal peptide. Neuroscience. 1995;65:943–946.

    Article  PubMed  CAS  Google Scholar 

  48. Sengul G, Coskun S, Cakir M, Coban MK, et al. Neuroprotective effect of ACE inhibitors in glutamate-induced neurotoxicity: rat neuron culture study. Turk Neurosurg.. 2011;21:367–371.

    PubMed  Google Scholar 

  49. Townsend DM, Tew KD, Tapiero H. The importance of glutathione in human disease. Biomed Pharmacother. 2003;57:145–155.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by Fundação Araucaria—PR and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Pharmacy, Universidade Estadual de Maringá, Maringá, PR, Brazil

    Catchia Hermes-Uliana, Camila Caviquioli Sehaber & Heber Amilcar Martins

  2. Department of Biology, Universidade Estadual de Maringá, Maringá, PR, Brazil

    Cynthia Priscilla do Nascimento Bonato Panizzon

  3. Department of Clinical Analysis and Biomedicine, Universidade Estadual de Maringá, Maringá, PR, Brazil

    Aline Rosa Trevizan

  4. Laboratório de Plasticidade Neural Entérica, Bloco O33, Department of Morphological Sciences, Universidade Estadual de Maringá, Avenida Colombo, 5790, Maringá, PR, 87020-900, Brazil

    Francielle Veiga Ramalho & Jacqueline Nelisis Zanoni

Authors
  1. Catchia Hermes-Uliana
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cynthia Priscilla do Nascimento Bonato Panizzon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aline Rosa Trevizan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Camila Caviquioli Sehaber
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Francielle Veiga Ramalho
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Heber Amilcar Martins
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jacqueline Nelisis Zanoni
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jacqueline Nelisis Zanoni.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hermes-Uliana, C., Panizzon, C.P.N.B., Trevizan, A.R. et al. Is l-Glutathione More Effective Than l-Glutamine in Preventing Enteric Diabetic Neuropathy?. Dig Dis Sci 59, 937–948 (2014). https://doi.org/10.1007/s10620-013-2993-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-013-2993-2

Keywords

Search

Navigation