Abstract
Lectins are proteins capable of reversible binding to carbohydrates or glycoconjugates. In the central nervous system of mammals, lectins with affinity for mannose/glucose or galactose can modulate cellular communication. ConBr, a lectin isolated from the seeds of Canavalia brasiliensis, previously showed antidepressant effect in the forced swimming test in mice, with involvement of the monoaminergic system. In this study, we investigated the neuroprotective effects of ConBr against quinolinic acid (QA), a well-known NMDA agonist that produces severe neurotoxicity when administered in vivo. ConBr (10 μg/site) administered via intracerebroventricular (i.c.v.) showed a neuroprotective activity against seizures induced by QA (36.8 nmol/site; i.c.v.) when administered 15 min prior to QA, with a percentage of protection around 50%. ConBr was also able to significantly decrease the severity of the seizures but without changes in the latency of the first convulsion or the duration of the seizures. This effect was dependent on the structural integrity of the ConBr protein and its binding capacity to oligosaccharides residues. ConA, a lectin with high similarity to ConBr, did not reverse the QA-induced seizures. Moreover, ConBr was able to protect against hippocampal cell death caused by QA, which was measured by propidium iodide incorporation. QA caused activation of JNK2 and improved the phosphorylation of Ser831 and 845 on the AMPA receptor GluR1 subunit, and both of these effects were counteracted by ConBr. Our data suggest that the lectin ConBr may exert a modulatory action on NMDA receptors, which inhibits its activity in response to QA.
Similar content being viewed by others
References
Varki A (1993) Biological roles of oligosaccharides: all of the theories are correct. Glycobiology 3:97–130
Breen KC, Coughlan CM, Hayes FD (1998) The role of glycoproteins in neural development function, and disease. Mol Neurobiol 16:163–220
Matthies H Jr, Kretlow J, Matthies H et al (1999) Glycosylation of proteins during a critical time window is necessary for the maintenance of long-term potentiation in the hippocampal CA1 region. Neuroscience 91:175–183
Lau A, Tymianski M (2010) Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch 460:525–542
Hullebroeck MF, Hampson DR (1992) Characterization of the oligosaccharide side chains on kainate binding proteins and AMPA receptors. Brain Res 590:187–192
Standley S, Baudry M (2000) The role of glycosylation in ionotropic glutamate receptor ligand binding, function, and trafficking. Cell Mol Life Sci 57:1508–1516
Hardingham GE, Bading H (2010) Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 11:682–696
Foster KA, McLaughlin N, Edbauer D et al (2010) Distinct roles of NR2A and NR2B cytoplasmic tails in long-term potentiation. J Neurosci 30:2676–2678
Kawamoto S, Hattori S, Sakimura K et al (1995) N Linked glycosylation of the AMPA-selective glutamate receptor channel alpha2 subunit is essential for essential for the acquisition of ligand-binding activity. J Neurochem 64:1258–1266
Laurie DJ, Bartke I, Schoepfer R et al (1997) Regional, developmental and interspecies expression of the four NMDAR2 subunits examined using monoclonal antibodies. Mol Brain Res 51:23
Cavada BS, Barbosa T, Arruda S et al (2001) Revisiting proteus: do minor changes in lectin structure matter in biological activity? Lessons from and potential biotechnological uses of the Diocleinae subtribe lectins. Curr Prot Pep Sci 2:1–13
Loris R (2002) Principles of structures of animal and plant lectins. Biochim Biophys Acta 1572:198–208
Ambrosi M, Cameron NR, Davis BG (2005) Lectins: tools for the molecular understanding of the glycocode. Org Biomol Chem 3:1593–1608
Sumner JB, Howell SF (1936) Identification of hemagglutinin of Jack Bean with Concanavalin A. J Bacteriol 32:227–237
Edelman GM, Cunningham BA, Reeke GN et al (1972) The covalent and three-dimensional structure of concanavalin A. Proc Natl Acad Sci USA 69:2580–2584
Hardman KD, Ainsworth CF (1972) Structure of concanavalin A at 2.4-A resolution. Biochemistry 11:4910–4919
Derewenda Z, Yariv J, Helliwell JR et al (1989) The structure of the saccharide-binding site of concanavalin A. EMBO J 8:2189–2193
Lin SS, Levitan IB (1991) Concanavalin A: a tool to investigate neuronal plasticity. Trends Neurosci 14:273–277
Scherer WJ, Udin SB (1994) Concanavalin A reduces habituation in the tectum of the frog. Brain Res 667:209–215
Kirner A, Deutsch S, Weiler E et al (2003) Concanavalin A application to the olfactory epithelium reveals different sensory neuron populations for the odour pair D- and L-carvone. Behav Brain Res 138:201–206
Suzuki T, Okumura-Noji K (1995) NMDA receptor subunits epsilon 1 (NR2A) and epsilon 2 (NR2B) are substrates for Fyn in the postsynaptic density fraction isolated from the rat brain. Biochem Biophys Res Commun 216:582–588
Clark RA, Gurd JW, Bissoon N et al (1998) Identification of lectin-purified neural glycoproteins, GPs 180, 116, and 110, with NMDA and AMPA receptor subunits: conservation of glycosylation at the synapse. J Neurochem 70:2594–2605
Partin KM, Patneau DK, Winters CA et al (1993) Selective modulation of desensitization at AMPA versus kainate receptors by cyclothiazide and concanavalin A. Neuron 11:1069–1082
Hoffman KB, Kessler M, Ta J et al (1998) Mannose-specific lectins modulate ligand binding to AMPA-type glutamate receptors. Brain Res 795:105–111
Thalhammer A, Everts I, Hollmann M (2002) Inhibition by lectins of glutamate receptor desensitization is determined by the lectin’s sugar specificity at kainate but not AMPA receptors. Mol Cell Neurosci 21:521–533
Yue KT, MacDonald JF, Pekhletski R et al (1995) Differential effects of lectins on recombinant glutamate receptors. Eur J Pharmacol 291:229–235
Everts I, Petroski R, Kizelsztein P et al (1999) Lectin-induced inhibition of desensitization of the kainate receptor GluR6 depends on the activation state and can be mediated by a single native or ectopic N-linked carbohydrate side chain. J Neurosci 19:916–927
Fay AM, Bowie D (2006) Concanavalin-A reports agonist-induced conformational changes in the intact GluR6 kainate receptor. J Physiol 572:201–213
Everts I, Villmann C, Hollmann M (1997) N-Glycosylation is not a prerequisite for glutamate receptor function but Is essential for lectin modulation. Mol Pharmacol 52:861–873
Sanz-Aparicio J, Hermoso J, Granjeiro TB et al (1997) The crystal structure of Canavalia brasiliensis lectin suggests a correlation between its quaternary conformation and its distinct biological properties from Concanavalin A. FEBS Letters 405:114–118
Barauna SC, Kaster MP, Heckert BT et al (2006) Antidepressant-like effect of lectin from Canavalia brasiliensis (ConBr) administered centrally in mice. Pharmacol Biochem Behav 85:160–169
Hardingham GE (2009) Coupling of the NMDA receptor to neuroprotective and neurodestructive events. Biochem Soc Trans 37:1147–1160
Schwarcz R, Pellicciari R (2002) Manipulation of brain kynurenines: glial targets, neuronal effects, and clinical opportunities. J Pharmacol Exp Ther 303:1–10
Schwarcz R, Guidetti P, Sathyasaikumar KV et al (2010) Of mice, rats and men: revisiting the quinolinic acid hypothesis of Huntington’s disease. Prog Neurobiol 90:230–245
Tavares RG, Schmidt AP, Tasca CI et al (2008) Quinolinic acid-induced seizures stimulate glutamate uptake into synaptic vesicles from rat brain: effects prevented by guanine-based purines. Neurochem Res 33:97–102
Tavares RG, Schmidt AP, Abud J et al (2005) In vivo quinolinic acid increases synaptosomal glutamate release in rats: reversal by guanosine. Neurochem Res 30:439–444
Moreira RA, Cavada BS (1984) Lectin from Canavalia brasiliensis Mart. Isolation, characterization and behavior during germination. Biol Plant Praga Checoslov 26:113–120
Schmidt AP, Lara DR, de FariaMaraschin J et al (2000) Guanosine and GMP prevent seizures induced by quinolinic acid in mice. Brain Res 864:40–43
Cruz SL, Gauthereau MY, Camacho-Munoz C et al (2003) Effects of inhaled toluene and 1, 1, 1-trichloroethane on seizures and death produced by N-methyl-d-aspartic acid in mice. Behav Brain Res 140:195–202
Marganella C, Bruno V, Matrisciano F et al (2005) Comparative effects of levobupivacaine and racemic bupivacaine on excitotoxic neuronal death in culture and N-methyl-D-aspartate-induced seizures in mice. Eur J Pharmacol 518:111–115
Cordova FM, Rodrigues AL, Giacomelli MB et al (2004) Lead stimulates ERK1/2 and p38MAPK phosphorylation in the hippocampus of immature rats. Brain Res 998:65–72
Molz S, Decker H, Dal-Cim T et al (2008) Glutamate-induced toxicity in hippocampal slices involves apoptotic features and p38 MAPK signaling. Neurochem Res 33:27–36
Boeck CR, Ganzella M, Lottermann A et al (2004) NMDA preconditioning protects against seizures and hippocampal neurotoxicity induced by quinolinic acid in mice. Epilepsia 45:745–750
Oliveira CS, Rigon AP, Leal RB et al (2008) The activation of ERK1/2 and p38 mitogen-activated protein kinases is dynamically regulated in the developing rat visual system. Int J Dev Neurosci 26:355–362
Peterson GL (1977) A simplification of the protein assay method of Lowry et al. which is more generally applicable. Anal Biochem 83:346–356
Bjerrum OJ, Heegaard NHH (1988) CRC handbook of immunoblotting of proteins, vol I: Technical Descriptions. CRC Press, Boca Raton, FL
Rigon AP, Cordova FM, Oliveira CS et al (2008) Neurotoxicity of cadmium on immature hippocampus and a neuroprotective role for p38 MAPK. Neurotoxicology 29:727–734
Posser T, de Aguiar CB, Garcez RC et al (2007) Exposure of C6 glioma cells to Pb(II) increases the phosphorylation of p38(MAPK) and JNK1/2 but not of ERK1/2. Arch Toxicol 81:407–414
Ferrer I, Blanco R, Carmona M (2001) Differential expression of active, phosphorylation-dependent MAP kinases, MAPK/ERK, SAPK/JNK and p38, and specific transcription factor substrates following quinolinic acid excitotoxicity in the rat. Mol Brain Res 94:48–58
Pierozan P, Zamoner A, Soska AK et al (2010) Acute intrastriatal administration of quinolinic acid provokes hyperphosphorylation of cytoskeletal intermediate filament proteins in astrocytes and neurons of rats. Exp Neurol 224:188–196
Bento CAM, Cavada BS, Oliveira JTA et al (1993) Rat paw edema and leucocyte migration induced by plant lectins. Agents Actions 38:48–54
Rodriguez D, Cavada BS, Abreu-de-Oliveira JT et al (1992) Differences in macrophage stimulation and leukocyte accumulation in response to intraperitoneal administration of glucose/mannose-binding plant lectins. Braz J Med Biol Res 25:823–826
Barbosa T, Arruda S, Cavada B et al (2001) In vivo lymphocyte activation and apoptosis by lectins of the diocleinaesubtribo. Mem Inst Oswaldo Cruz 96:673–678
Ferreira RR, Cavada BS, Moreira RA et al (1996) Characteristics of the histamine release from hamster cheek pouch mast cells stimulated by lectins from Brazilian beans and concanavalin A. Inflamm Res 45:442–447
Lopes FC, Cavada BS, Pinto VP et al (2005) Differential effect of plant lectins on mast cells of different origins. Braz J Med Biol Res 38:935–941
Andrade JL, Arruda S, Barbosa T et al (1999) Lectin-induced nitric oxide production. Cell Immunol 194:98–102
Pemberton KE, Belcher SM, Ripellino JA, et.al. (1998) High-affinity kainate-type ion channels in rat cerebellar granule cells. J Physiol 510(Pt 2):401–420
Machaidze GG, Mikeladze D (2001) Different effects of lectins on the ligand binding of the NMDA receptors and sigma sites in rat brain hippocampus synaptic membranes. Neurochem Res 26:457–462
Lapin IP (1978) Stimulant and convulsive effects of kynurenines injected into brain ventricles in mice. J Neural Trans 42:37–43
Stone TW, Perkins MN (1981) Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS. Eur J Pharmacol 72:411–412
Kuroki Y, Fukushima K, Kanda Y, Mizuno K, Watanabe Y (2001) Neuroprotection by estrogen via extracellular signal-regulated kinase against quinolinic acid-induced cell death in the rat hippocampus. Eur J Neurosci 13:472–476
Brecht S, Kirchhof R, Chromik A, Willesen M, Nicolaus T, Raivich G, Wessig J, Waetzig V, Goetz M, Claussen M, Pearse D, Kuan CY, Vaudano E, Behrens A, Wagner E, Flavell RA, Davis RJ, Herdegen T (2005) Specific pathophysiological functions of JNK isoforms in the brain. Eur J Neurosci 21:363–377
Zhao Y, Herdegen T (2009) Cerebral ischemia provokes a profound exchange of activated JNK isoforms in brain mitochondria. Mol Cell Neurosci 41:186–195
Waetzig V, Zhao Y, Herdegen T (2006) The bright side of JNKs-Multitalented mediators in neuronal sprouting, brain development and nerve fiber regeneration. Prog Neurobiol 80:84–97
Kessels HW, Malinow R (2009) Synaptic AMPA receptor plasticity and behavior. Neuron 61:340–350
Santos SD, Carvalho AL, Caldeira MV et al (2009) Regulation of AMPA receptors and synaptic plasticity. Neuroscience 158:105–125
Zanetta JP, Meyer A, Kuchler S et al (1987) Isolation and immunochemical study of a soluble cerebellar lectin delineating its structure and function. J Neurochem 49:1250–1257
Marschal P, Reeber A, Neeser JR et al (1989) Carbohydrate and glycoprotein specificity of two endogenous cerebellar lectins. Biochimie 71:645–653
Lehmann S, Kuchler S, Theveniau M et al (1990) An endogenous lectin and one of its neuronal glycoprotein ligands are involved in contact guidance of neuron migration. Proc Natl Acad Sci USA 87:6455–6459
Kuchler S, Lehmann S, Vincendon G et al (1992) Endogenous lectin cerebellar soluble lectin involved in myelination is absent from nonmyelinating Schwann cells. J Neurochem 58:1768–1772
Lekishvili T, Hesketh S, Brazier MW et al (2006) Mouse galectin-1 inhibits the toxicity of glutamate by modifying NR1 NMDA receptor expression. Eur J Neurosci 24:3017–3025
Acknowledgments
CNPq (#305194/2010-0), CAPES/PROCAD (#167/2007), CAPES/DGU (#173/2008), FINEP research grant “Rede Instituto Brasileiro de Neurociência (IBN-Net; #01.06.0842-00”) and FAPESC (# 6336/2011-3) supported this work. EHT, BSC, CIT and RBL are recipients of CNPq fellowships.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Russi, M.A., Vandresen-Filho, S., Rieger, D.K. et al. ConBr, a Lectin from Canavalia brasiliensis Seeds, Protects Against Quinolinic Acid-Induced Seizures in Mice. Neurochem Res 37, 288–297 (2012). https://doi.org/10.1007/s11064-011-0608-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-011-0608-x