Skip to main content

Advertisement

SpringerLink
Log in

Increased inflammatory markers in brain and blood of rats subjected to acute homocysteine administration

  • Original Paper
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Hyperhomocysteinemia plays an etiologic role in the pathogenesis of disorders, including homocystinuria and neurodegenerative and cardiovascular diseases. In the present study, we studied the effect of acute administration of homocysteine, similar to that found in homocystinuria, on parameters of inflammation such as cytokines (TNF-α, IL-1β and IL-6), chemokine CCL2 (MCP-1), nitrite and acute phase-proteins (C-reactive protein and α1-Acid glycoprotein) levels in brain and blood of rats. In addition, a differential count of blood leukocytes was performed. Wistar rats, aged 29 days, received a single subcutaneous injection of saline (control) or homocysteine (0.6 µmol/g body weight). Fifteen minutes, 1 h, 6 h or 12 h after the injection, the rats were sacrificed and serum, hippocampus and cerebral cortex were used. Results showed that homocysteine significantly increased proinflammatory cytokines (TNF-α, IL-1β and IL-6) and chemokine CCL2 (MCP-1) in serum, hippocampus and cerebral cortex. Nitrite levels also increased in hippocampus and cerebral cortex at 15 min, 1 h and 6 h, but not 12 h after homocysteine administration. Acute phase-protein levels were not altered by homocysteine. The percentage of neutrophils and monocytes significantly increased in blood at 15 min and 1 h, but not at 6 h and 12 h after acute hyperhomocysteinemia, when compared to the control group. Our results showed that acute administration of homocysteine increased inflammatory parameters, suggesting that inflammation might be associated, at least in part, with the neuronal and cardiovascular dysfunctions observed in homocystinuric patients.

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

  • Argenbright LW, Barton RW (1992) Interaction of leukocyte integrins with intercellular adhesion molecule I in the production of inflammatory vascular injury in vivo: the Schwartzmann reaction revisited. J Clin Invest 89:259–272

    Article  CAS  PubMed  Google Scholar 

  • Au-Yeung KKW, Woo CWH, Sung FL, Yip JCW, Siow YL, Karmin O (2003) Hyperhomocysteinemia activates nuclear factor-κB in endothelial cells via oxidative stress. Circ Res 94:28–36

    Article  PubMed  CAS  Google Scholar 

  • Dalal S, Parkin SM, Homer-Vanniasinkam S, Nicolaou A (2003) Effect of homocysteine on cytokine production by human endothelial cells and monocytes. Ann Clin Biochem 40:534–541

    Article  CAS  PubMed  Google Scholar 

  • de Jong SC, Stehouwer CD, van der Berg M, Vischer UM, Rauwerda JA, Emeis JJ (1997) Endothelial marker proteins in hyperhomocysteinemia. Thromb Haemost 78:1332–1337

    PubMed  Google Scholar 

  • Dudman NPB, Temple SE, Guo XW, Fu W, Perry MA (1999) Homocysteine enhances neutrophil-endothelial interactions in both cultured human cells and rats in vivo. Circ Res 84:409–416

    CAS  PubMed  Google Scholar 

  • Frode-Saleh TS, Calixto JB, Medeiros YS (1999) Analysis of the inflammatory response induced by substance P in the mouse pleural cavity. Peptides 20:259–265

    Article  CAS  PubMed  Google Scholar 

  • Ghirnikar RS, Lee YL, Eng LF (1998) Inflammation in traumatic brain injury: role of cytokines and chemokines. Neurochem Res 23:329–340

    Article  CAS  PubMed  Google Scholar 

  • Giulian D, Chen J, Ingeman JE, George JK, Noponen M (1989) The role of mononuclear phagocytes in wound healing after traumatic injury to the adult mammalian brain. J Neurosci 9:4416–4429

    CAS  PubMed  Google Scholar 

  • Gori AM, Corsi AM, Fedi S, Gazzini A, Sofi F, Bartali B, Bandinelli S, Gensini GF, Abbate R, Ferrucci L (2005) A proinflammatory state is associated with hyperhomocysteinemia in the elderly. Am J Clin Nutr 82:335–341

    CAS  PubMed  Google Scholar 

  • Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite and [15N]nitrate in biological fluids. Anal Biochem 126:131–138

    Article  CAS  PubMed  Google Scholar 

  • Halliwell B, Gutteridge JMC (2007) Free radicals in biology and medicine. Oxford University Press, Oxford, pp 218–220

    Google Scholar 

  • Jatakanon A, Lalloo UG, Lim S, Chung KF, Barnes PJ (1999) Increased neutrophils and cytokines, TNF-a and IL-8, in induced sputum of non-asthmatic patients with chronic dry cough. Thorax 54:234–237

    Article  CAS  PubMed  Google Scholar 

  • Keane MP, Strieter RM (2000) Chemokine signaling in inflammation. Crit Care Med 28(4 Suppl):N13–N26

    Article  CAS  PubMed  Google Scholar 

  • Lerouet D, Beray-Berthat V, Palmier B, Plotkine M, Margaill I (2002) Changes in oxidative stress, iNOS activity and neutrophil infiltration in severe transient focal cerebral ischemia in rats. Brain Res 958:166–175

    Article  CAS  PubMed  Google Scholar 

  • Lindmark E, Diderholm E, Wallentin L, Siegbahn A (2001) Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease: effects of an early invasive or noninvasive strategy. JAMA 286:2107–2113

    Article  CAS  PubMed  Google Scholar 

  • Lipton SA, Kim WK, Choi YB, Kumar S, D’Emilia DM, Rayudu PV, Arnelle DR, Stamler JS (1997) Neurotoxicity associated with dual actions of homocyteine at the N-methyl-D-aspartate receptor. Proc Natl Acad Sci 94:5923–5928

    Article  CAS  PubMed  Google Scholar 

  • Liu B, Hong JS (2003) Role of microglia in inflammation-mediated neurodegenerative disease: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther 304:1–7

    Article  CAS  PubMed  Google Scholar 

  • Liu X, Luo F, Li J, Wu W, Li L, Chen H (2008) Homocysteine induces connective tissue growth factor expression in vascular smooth muscle cells. J Thromb Haemost 6:184–192

    Article  CAS  PubMed  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randal RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–267

    CAS  PubMed  Google Scholar 

  • Lucas SM, Rothwell NJ, Gibson RM (2006) The role of inflammation in CNS injury and disease. Br J Pharmacol 147(Suppl 1):S232–S240

    Article  CAS  PubMed  Google Scholar 

  • Mattson MP, Shea TB (2003) Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends Neurosci 26:137–146

    Article  CAS  PubMed  Google Scholar 

  • Matté C, Monteiro SC, Calcagnotto T, Bavaresco CS, Netto CA, Wyse AT (2004) In vivo and in vitro effects of homocysteine on Na+, K+-ATPase activity in parietal, prefrontal and cingulated cortex of young rats. Int J Dev Neurosci 22:185–190

    Article  PubMed  CAS  Google Scholar 

  • Matté C, Scherer EBS, Stefanello FM, Barschak AG, Vargas CR, Netto CA, Wyse ATS (2007) Concurrent folate treatment prevents Na+K+-ATPase activity inhibition and memory impairments caused by chronic hyperhomocysteinemia during rat development. Int J Dev Neurosci 25:545–552

    Article  PubMed  CAS  Google Scholar 

  • Matté C, Mackedanz V, Stefanello FM, Scherer EBS, Andreazza AC, Zanotto C, Moro AM, Garcia SC, Gonçalves CA, Erdtmann B, Salvador M, Wyse AT (2009) Chronic hyperhomocysteinemia alters antioxidant defenses and increases DNA damage in brain and blood of rats: protective effect of folic acid. Neurochem Int 54:7–13

    Article  PubMed  CAS  Google Scholar 

  • Mudd SH, Levy HL, Skovby F (2001) Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular basis of inherited disease, vol 2. McGraw-Hill, New York, pp 1279–1327

    Google Scholar 

  • Napoli C, de Nigris F, Palinski W (2001) Multiple role of reactive oxygen species in the arterial wall. J Cell Biochem 82:674–682

    Article  CAS  PubMed  Google Scholar 

  • Patti G, Ambrosio A, Dobrina A, Dicuonzo G, Giansante C, Fiotti N, Abbate A, Guarnieri G, Di Sciascio G (2002) Interleukin-1 receptor antagonist: a sensitive markers of instability in patients with coronary artery disease. J Thomb Thrombolysis 14:139–143

    Article  Google Scholar 

  • Poddar R, Sivasubramanian N, DiBello PM, Robinson K, Jacobsen DW (2001) Homocysteine induces expression and secretion of monocyte chemoattractant protein-1 and interleukin-8 in human aortic endothelial cells: implications for vascular disease. Circulation 103:2717–2723

    CAS  PubMed  Google Scholar 

  • Pollmacher T, Haack M, Schuld A, Reichenberg A, Yirmiya R (2002) Low levels of circulating inflammatory cytokines—do they affect human brain functions? Brain Behav Immun 16:525–532

    Article  CAS  PubMed  Google Scholar 

  • Ridker PM, Rifai N, Stampfer MJ, Hennekens CH (2000a) Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 101:1767–1772

    CAS  Google Scholar 

  • Ridker PM, Hennekens CH, Buring JE, Rifai N (2000b) C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 342:836–843

    Article  CAS  Google Scholar 

  • Rothwell NJ, Luheshi GN (2000) Interleukin 1 in the brain: biology, pathology and therapeutic target. Trends Neurosci 23:618–625

    Article  CAS  PubMed  Google Scholar 

  • Streck EL, Matté C, Vieira PS, Rombaldi F, Wannmacher CM, Wajner M, Wyse AT (2002) Reduction of Na+, K+-ATPase activity in hippocampus of rats subjected to chemically induced hyperhomocysteinemia. Neurochem Res 27:1593–1598

    Article  CAS  PubMed  Google Scholar 

  • Streck EL, Vieira PS, Wannmacher CM, Dutra-Filho CS, Wajner M, Wyse AT (2003) In vitro effect of homocysteine on some parameters of oxidative stress in rat hippocampus. Metab Brain Dis 18:147–154

    Article  CAS  PubMed  Google Scholar 

  • Suffredini AF, Fantuzzi G, Badolato R, Oppenheim JJ, O’Grady NP (1999) New insights into the biology of the acute phase response. J Clin Immunol 19:203–214

    Article  CAS  PubMed  Google Scholar 

  • Sung FL, Slow YL, Wang G, Lynn EG, O K (2001) Homocysteine stimulates the expression of monocyte chemoattractant protein-1 in endothelial cells leading to enhanced monocyte chemotaxis. Mol Cell Biochem 216:121–128

    Article  CAS  PubMed  Google Scholar 

  • Thomas PS, Yates DH, Barnes PJ (1995) Tumor necrosis factor-a increases airway responsiveness and sputum neutrophilia in normal human subjects. Am J Respir Crit Care Med 152:76–80

    CAS  PubMed  Google Scholar 

  • Tyagi N, Gillespie W, Vacek JC, Sen U, Tyagi SC, Lominadze D (2009) Activation of GABA-A receptor ameliorates homocysteine-induced MMP-9 by ERK pathway. J Cell Physiol 220:257–266

    Article  CAS  PubMed  Google Scholar 

  • Upchurch GR Jr, Welch GN, Fabian AJ, Freedman JE, Johnson JL, Keaney JF Jr, Loscalzo J (1997) Homocysteine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem 272:17012–17017

    Article  CAS  PubMed  Google Scholar 

  • Wang G, Siow YL, O K (2000) Homocysteine stimulates nuclear factor kappaB activity and monocyte chemoattractant protein-1 expression in vascular smooth muscle cells: possible role for protein kinase C. Biochem J 352:817–826

    Article  CAS  PubMed  Google Scholar 

  • Wang G, Siow YL, O K (2001) Homocysteine induces monocyte chemoattractant protein-1 expression by activating NF-kappaB in THP-1 macrophages. Am J Physiol Heart Circ Physiol 280:H2840–H2847

    CAS  PubMed  Google Scholar 

  • Wang G, Woo CW, Sung FL, Siow YL, O K (2002) Increased monocyte adhesion to aortic endothelium in rats with hyperhomocysteinemia: role of chemokine and adhesion molecules. Arterioscler Thromb Vasc Biol 22:1777–1783

    Article  CAS  PubMed  Google Scholar 

  • Weiss N (2005) Mechanisms of increased vascular oxidant stress in hyperhomocysteinemia and its impact on endothelial function. Curr Drug Metab 6:27–36

    Article  CAS  PubMed  Google Scholar 

  • Welch GN, Loscalzo J (1998) Homocysteine and atherothrombosis. N Engl J Med 338:1042–1050

    Article  CAS  PubMed  Google Scholar 

  • Weiss N, Heydrick SJ, Postea O, Keller C, Keaney JFJ, Loscalzo J (2003) Influence of hyperhomocysteinemia on the cellular redox state: impact on homocysteine-induced endothelial dysfunction. Clin Chem Lab Med 41:1455–1461

    Article  CAS  PubMed  Google Scholar 

  • Wyse AT, Zugno AI, Streck EI, Matté C, Calcagnotto T, Wannmacher CM, Wajner M (2002) Inhibition of Na+, K+-ATPase activity in hippocampus of rats subjected to acute administration of homocysteine is prevented by vitamins E and C treatment. Neurochem Res 27:1685–1689

    Article  CAS  PubMed  Google Scholar 

  • Yun J, Kim JY, Kim OY, Jang Y, Chae JS, Kwak JH, Lim HH, Park HY, Lee SH, Lee JH (2009) Associations of plasma homocysteine level with brachial-ankle pulse wave velocity, LDL atherogenicity, and inflammation profile in healthy men. Nutr Metab Cardiovasc Dis 22:1–8

    Google Scholar 

  • Zhang Q, Zeng X, Guo J, Wang X (2001) Effects of homocysteine on murine splenic B lymphocyte proliferation and its signal transduction mechanism. Cardiovasc Res 52:328–336

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Jin M, Hu X, Zhu J (2006) Homocysteine stimulates nuclear factor kB activity and interleukin-6 expression in rat vascular smooth muscle cells. Cell Biol Int 30:592–597

    Article  CAS  PubMed  Google Scholar 

  • Zhou Z, Connell MC, MacEwan DJ (2007) TNFR1-induced NF-kappaB, but not ERK, p38MAPK or JNK activation, mediates TNF-induced ICAM-1 and VCAM-1 expression on endothelial cells. Cell Signal 19:1238–1248

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported in part by grants from Conselho Nacional de Desenvolvimento Científico Tecnológico (CNPq-Brazil) and Instituto Nacional de Ciências e Tecnologia para Excitotoxicidade e Neuroproteção (Processo n0: 573677/2008-5).

Author information

Authors and Affiliations

  1. Laboratório de Neuroproteção e Doenças Metabólicas, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil

    Aline A. da Cunha, Andréa G. K. Ferreira & Angela T. S. Wyse

Authors
  1. Aline A. da Cunha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andréa G. K. Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Angela T. S. Wyse
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Angela T. S. Wyse.

Rights and permissions

Reprints and permissions

About this article

Cite this article

da Cunha, A.A., Ferreira, A.G.K. & Wyse, A.T.S. Increased inflammatory markers in brain and blood of rats subjected to acute homocysteine administration. Metab Brain Dis 25, 199–206 (2010). https://doi.org/10.1007/s11011-010-9188-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-010-9188-8

Keywords

Search

Navigation