Abstract
This in vivo microdialysis study compared the effects of NMDA and d,l-homocysteine (Hcy) administered via dialysis medium on 45Ca efflux from prelabeled rabbit hippocampus. Application of these agonists evoked dose-dependent, and sensitive to MK-801, opposite effects: NMDA decreased the 45Ca radioactivity in the dialysate, whereas Hcy induced the release of 45Ca. The latter effect was potentiated by glycine, inhibited by the antagonist of group I metabotropic glutamate receptors (mGluR) LY367385, and mimicked by t-ADA, an agonist of these receptors. Electron microscopic examination of pyramidal neurones in the CA1 sector of the hippocampus in the vicinity of the microdialysis probe after NMDA application demonstrated swelling of mitochondria, which was prevented by cyclosporin A. This study shows, for the first time, Hcy-induced activation of both group I mGluR and NMDA receptors, which may play a role in acute Hcy neurotoxicity. We present new applications of brain microdialysis in studies on excitotoxicity and neuroprotection.
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REFERENCES
Choi, D. W. 1987. Ionic dependence of glutamate neurotoxicity. J. Neurosci. 7:369–379.
Choi, D. W. 1988. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1:623–634.
Choi, D. W. 1995. Calcium: Still center-stage in hypoxic-is-chemic neuronal death. Trends Neurosci. 18:58–60.
Choi, D. W. 1994. Calcium and excitotoxic neuronal injury, Ann. N.Y. Acad. Sci. 747:162–171.
Gosh, A. and Greenberg, M. E. 1995. Calcium signalling in neurons: Molecular mechanisms and cellular consequences. Science 268:239–247.
Berridge, M. J., Bootman, M. D., and Lipp, P. 1998. Calcium: A life and death signal. Nature 395:645–648.
Mayer, M. L. and Westbrook, G. L. 1987. Permeation and block of N-methyl-D-aspartic acid receptor channels by divalent cations in mouse cultured central neurons. J. Physiol. 394:500–527.
Michaels, R. L. and Rothman, S. M. 1990. Glutamate neurotoxicity in vitro: Antagonist pharmacology and intracellular calcium concentrations. J. Neurosci. 10:283–292.
Monaghan, D. T., Bridges, R. J., and Cotman, C. W. 1989. The excitatory amino acid receptors: Their classes, pharmacology, and distinct properties in the function of the central nervous system. Annu. Rev. Pharmacol. Toxicol. 29:365–402.
Conn, P. J. and Pin, J. P. 1997. Pharmacology and functions of metabotropic glutamate receptors. Annu. Rev. Pharmacol. Toxicol. 37:205–237.
Schoepp, D. D., Jane, D. E., and Monn, J. A. 1999. Pharmacological agents acting at subtypes of metabotropic glutamate receptors. Neuropharmacology 38:1431–1476.
Bond, A., O'Neill, M. J., Hicks, C. A., Monn, J. A., and Lodge, D. 1998. Neuroprotective effects of a systemically active group II metabotropic glutamate receptor agonist LY354740 in a gerbil model of global ischemia. Neuroreport 9:1191–1193.
Bond, A., Jones, N. M., Hicks, C. A., Whiffin, G. M., Ward, M. A., O'Neill, M. F., Kingston, A. E., Monn, J. A., Ornstein, P. L., Schoepp, D. D., Lodge, D., and O'Neill, M. J. 2000. Neuroprotective effects of LY379268, a selective mGlu2/3 receptor agonist: Investigations into possible mechanism of action in vivo. J. Pharmacol. Exp. Ther. 294:800–809.
Montoliu, C., Llansola, M., Cucarella, C., Grisolia, S., and Felipo, V. 1997. Activation of the metabotropic glutamate receptor mGluR5 prevents glutamate toxicity in primary cultures of cerebellar neurons. J. Pharmacol. Exp. Ther. 281:643–647.
Cai, Z., Xiao, F., Fratkin, J. D., and Rhodes, P. G. 1999. Protection of neonatal rat brain from hypoxic-ischemic injury by LY379268, a group II metabotropic glutamate receptor agonist. Neuroreport 10:3927–3931.
Cambonie, G., Laplanche, L., Kamenka, J. M., and Barbanel, G. 2000. N-Methyl-D-aspartate but not glutamate induces the release of hydroxyl radicals in the neonatal rat: Modulation by group I metabotropic glutamate receptors. J. Neurosci. Res. 62:84–90.
Pullan, L. M., Olney, J. W., Price, M. T., Compton, R. P., Hood, W. F., Michel, J., and Monahan, J. B. 1987. Excitatory amino acid receptor potency and subclass specificity of sulphur containing amino acids. J. Neurochem. 49:1301–1307.
Griffiths, R. 1990. Cysteine sulphinate (CSA) as an excitatory amino acid transmitter candidate in the mammalian central nervous system. Prog. Neurobiol. 35:313–323.
Do, K. Q., Mattenberger, M., Streit, P., and Cuenod, M. 1986. In vitro release of endogenous excitatory sulfur-containing amino acids from various rat brain regions. J. Neurochem. 46:779–786.
Porter, R. H. P. and Roberts, P. J. 1993. Glutamate metabotropic receptor activation in neonatal rat cerebral cortex by sulphur-containing axcitatory amino acids. Neurosci. Lett. 154:78–80.
Frandsen, A., Schousboe, A., and Griffiths, R. 1993. Cytotoxic actions and effects on intracellular Ca2+ and cGMP concentrations of sulphur-containing excitatory amino acids in cultured cerebral cortical neurons. J. Neurosci. Res. 34:331–339.
Seshadri, S., Beiser, A., Selhub, J., Jacques, P. F., Rosenberg, I. H., D'Agostino, R. B., Wilson, P. W. F., and Wolf, P. A. 2002. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N. Engl. J. Med. 346:476–483.
Scott, J. M. and Weir, D. G. 1998. Folic acid, homocysteine, and one-carbon metabolism: A review of the essential biochemistry. J. Cardiovasc. Risk 5:223–227.
Refsum, H., Ueland, P. M., Nygard, O., and Vollset, S. E. 1998. Homocysteine and cardiovascular disease. Annu. Rev. Med. 49:31–62.
Stampfer, M. J., Malinow, M. R., Willett, W. C., Newcomer, L. M., Upson, B., Ullmann, D., Tishler, P. V., and Hennekens, C. H. 1992. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 268:877–881.
Perry, I. J., Refsum, H., Morris, R. W., Ebrahim, S. B., Ueland, P. M., and Shaper, A. G. 1995. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet 346:1395–1398.
Watkins, D. and Rosenblatt, D. S. 1989. Functional methionine synthase defficiency (cdIE and cbIG): Clinical and biochemical heterogeneity. Am. J. Med. Genet. 34:427–434.
van den Berg, M., van der Knaap, M. S., Boers, G. H., Stehouwer, C. D., Rauwerda, J. A., and Valk, J. 1995. Hyperhomocysteinaemia, with reference to its neuroradiological aspects. Neuroradiology 37:403–411.
Duan, W., Ladenheim, B., Cutler, R. G., Kruman, I. I., Cadet, J. L., and Mattson, M. P. 2002. Dietary foliate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson's disease. J. Neurochem. 80:101–110.
Kruman, I. I., Culmsee, C., Chan, S. L., Kruman, Y., Guo, Z., Penix, L., and Mattson, M. P. 2000. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J. Neurosci. 20:6920–6926.
Kruman, I. I., Kumaravel, T. S., Lohani, A., Pedersen, W. A., Cutler, R. G., Kruman, Y., Haughey, N., Lee, J., Evans, M., and Mattson, M. P. 2002. Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer's disease. J. Neurosci. 22:1752–1762.
Folbergrová, J. 1993. Cerebral energy state of neonatal rats during seizures induced by homocysteine. Physiol. Res. 42:155–160.
Folbergrová, J. 1997. Anticonvulsant action of both NMDA and non-NMDA receptor antagonists against seizures induced by homocysteine in immature rats. Exp. Neurol. 145:442–450.
Kim, W.-K. and Pae, Y.-S. 1996. Involvement of N-methyl-D-aspartate receptor and free radical in homocysteine-mediated toxicity on rat cerebellar granule cells in culture. Neurosci. Lett. 216:117–120.
Lipton, S. A., Kim, W.-K., Choi, Y.-B., Kumar, S., D'Emilia, D. M., Rayudu, P. V., Arnelle, D. R., and Stamler, J. S. 1997. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc. Natl. Acad. Sci. USA 94:5923–5928.
Lazarewicz, J. W., Hagberg, H., and Hamberger, A. 1986. Extracellular calcium in the hippocampus of unanesthetized rabbits monitored with dialysis-perfusion. J. Neurosci. Methods 15:317–328.
Lazarewicz, J. W., Lehmann, A., Hagberg, H., and Hamberger, A. 1986. Effects of kainic acid on brain calcium fluxes studied in vivo and in vitro. J. Neurochem. 46:494–498.
Lazarewicz, J. W., Lehmann, A., and Hamberger, A. 1987. Effects of calcium entry blockers on kainate-induced changes in extracellular amino acids and Ca2+ in vivo. J. Neurosci. Res. 18:341–344.
Lehmann, A., Hagberg, H., Lazarewicz, J. W., Jacobson, I., and Hamberger, A. 1986. Alterations in extracellular amino acids and Ca2+ following excitotoxin administration and during status epilepticus. Pages 363–374, in Schwarcz, R. and Ben-Ari, Y. (eds), Advances in Experimental Medicine and Biology, Vol. 203, Excitatory Amino Acids and Epilepsy, Plenum Press, New York.
Butcher, S. P., Lazarewicz, J. W., and Hamberger, A. 1987. In vivo microdialysis studies on the effects of decortication and ex-citotoxic lesion on kainic acid-induced calcium fluxes, and exogenous amino acid release, in the rat striatum. J. Neurochem. 49:1355–1360.
Lazarewicz, J. W. and Salinska, E. 1993. Role of calcium in glutamate-mediated toxicity: Mechanisms of calcium fluxes in rabbit hippocampus in vivo investigated with microdialysis. Acta Neurobiol. Exp. 53:3–13.
Lazarewicz, J. W., Salinska, E., and Matyja, E. 1995. Ganglioside GMI prevents N-methyl-D-aspartate neurotoxicity in rabbit hippocampus in vivo: Effects on calcium homeostasis. Mol. Chem. Neuropathol. 24:165–179.
Lazarewicz, J. W., Rybkowski, W., Salinska, E., Gordon-Krajcer, W., Zieminska, E., Ziembowicz, A., Puka-Sundvall, M., and Hagberg, H. 1997. Generation of Ca2+ signal in NMDA receptors of rat and rabbit hippocampus in vivo: Ca2+ influx and mobilisation. Pages 361–367, in Teelken, A. W. and Kopf, J. (eds), Neurochemistry: Cellular, molecular and clinical aspects. The Proceedings of the 11th ESN Meeting Plenum Press, New York.
Salinska, E., Ziembowicz, A., Gordon-Krajcer, W., Skangiel-Kramska, J., Jablonska, B., Makarewicz, D., Zieminska, E., and Lazarewicz, J. W. 2000. Differences between rats and rabbits in NMDA receptor-mediated calcium signalling in hippocampal neurones. Brain Res. Bull. 53:813–819.
Kroemer, G., Zamzami, N., and Susin, S. A. 1997. Mitochondrial control of apoptosis. Immunol. Today 18:44–51.
Kristal, B. S. and Dubinsky, J. M. 1997. Mitochondrial permeability transition in the central nervous system: Induction by calcium cycling-dependent and-independent pathways. J. Neurochem. 69:524–538.
Uchino, H., Elmer, E., Uchino, K., Lindvall, O., and Siesjö, B. K. 1995. Cyclosporin A dramatically ameliorates CA1 hippocampal damage following transient forebrain ischaemia in the rat. Acta Physiol. Scand. 155:469–471.
Friberg, H., Ferrand-Drake, M., Bengtsson, F., Halestrap, A. P., and Wieloch, T. 1998. Cyclosporin A, but not FK 506, protects mitochondria and neurons against hypoglycemic damage and implicates the mitochondrial permeability transition in cell death. J. Neurosci. 18:5151–5159.
Begley, D. J., Squires, L. K., Zlokovic, B. V., Mitrovic, D. M., Hughes, C. C., Revest, P. A., and Greenwood, J. 1990. Permeability of the blood-brain barrier to the immunosuppressive cyclic peptide cyclosporin A. J. Neurochem. 55:1222–1230.
Nystrom, B., Karlsson, J. O., and Hamberger, A. 1988. Secretion of newly synthesized proteins into the extracellular fluid of the rabbit hippocampus. J. Neurosci. Res. 21:51–55.
Lazarewicz, J. W., Salinska, E., and Puka, M. 1992. Glycine enhances extracellular 45Ca2+ response to NMDA application investigated with microdialysis of rabbit hippocampus in vivo. Acta Neurobiol. Exp. 52:83–91.
Lindroth, P. and Mopper, K. 1979. High-performance liquid chromatographic determination of subpicomole amounts of amino acid by precolumn fluorescence derivatization with O-phthaldialdehyde. Anal. Chem. 51:1667–1674.
Lazarewicz, J. W., Rybkowski, W., Sadowski, M., Ziembowicz, A., Alaraj, M., Wegiel, J., and Wisniewski, H. W. 1998. N-Methyl-D-aspartate receptor-mediated, calcium-induced calcium release in rat dentate gyrus/CA4 in vivo. J. Neurosci. Res. 51:76–84.
Nakamura, T., Nakamura, K., Lasser-Ross, N., Barbara, J. G., Sandler, V. M., and Ross, W. N. 2000. Inositol 1,4,5–trisphosphate (IP3)-mediated Ca2+ release evoked by metabotropic agonists and backpropagating action potentials in hippocampal CA1 pyramidal neurons. J. Neurosci. 20:8365–8376.
Pisani, A., Gubellini, P., Bonsi, P., Conquet, F., Picconi, B., Centonze, D., Bernardi, G., and Calabresi, P. 2001. Metabotropic glutamate receptor 5 mediates the potentiation of N-methyl-D-aspartate responses in medium spiny striatal neurons. Neuroscience 106:579–587.
Miniaci, M. C., Bonsi, P., Tempia, F., Strata, P., and Pisani, A. 2001. Presynaptic modulation by group III metabotropic glutamate receptors (mGluRs) of the excitatory postsynaptic potential mediated by mGluR1 in rat cerebellar Purkinje cells. Neurosci. Lett. 310:61–65.
Mannaioni, G., Marino, M. J., Valenti, O., Traynelis, S. F., and Conn, P. J. 2001. Metabotropic glutamate receptors 1 and 5 differentially regulate CA1 pyramidal cell function. J. Neurosci. 21:5925–5934.
Kozikowski, A. P., Tuckmantel, W., Liao, Y., Manev, H., Ikonomovic, S., and Wroblewski, J. T. 1993. Synthesis and metabotropic receptor activity of the novel rigidified glutamate analogues (+) and (-)-trans-azetidine-2,4–dicarboxylic acid and their N-methyl derivatives. J. Med. Chem. 36:2706–2708.
Manahan-Vaughan, D., Reiser, M., Pin, J. P, Wilsch, V., Bockaert, J., Reymann, K. G., and Riedel, G. 1996. Physiological and pharmacological profile of trans-azetidine-2,4–dicarboxylic acid: Metabotropic glutamate receptor agonism and effects on long-term potentiation. Neuroscience 72:999–1008.
Manahan-Vaughan, D. and Reymann, K. G. 1996. Metabotropic glutamate receptor subtype agonists facilitate long-term potentiation within a distinct time window in the dentate gyrus in vivo. Neuroscience 74:723–731.
Klein, J., Reymann, K. G., and Riedel, G. 1997. Activation of phospholipases C and D by the novel metabotropic glutamate receptor agonist tADA. Neuropharmacology 36:261–263.
Contractor, A., Gereau, R. W., 4th, Green, T., and Heinemann, S. F. 1998. Direct effects of metabotropic glutamate receptor compounds on native and recombinant N-methyl-D-aspartate receptors. Proc. Natl. Acad. Sci. USA 95:8969–8974.
Masgrau, R., Servitja, J. M., Young, K. W., Pardo, R., Sarri, E., Nahorski, S. R., and Picatoste, F. 2001. Characterization of the metabotropic glutamate receptors mediating phospholipase C activation and calcium release in cerebellar granule cells: Calcium-dependence of the phospholipase C response. Eur. J. Neurosci. 13:248–256.
Aramori, I. and Nakanishi, S. 1992. Signal transduction and pharmacological characteristics of a metabotropic glutamate receptor, mGluR1, in transfected CHO cells. Neuron 8:757–765.
Gorman, A. and Griffiths, R. 1994. Sulphur-containing excitatory amino acid-stimulated inositol phosphate formation in primary cultures of cerebellar granule cells is mediated predominantly by N-methyl-D-aspartate receptors. Neuroscience 59:299–308.
Kingston, A. E., Lowndes, J., Evans, N., Clark, B., Tomlinson, R., Burnett, J. P., Mayne, N. G., Cockerham, S. L., and Lodge, D. 1998. Sulphur-containing amino acids are agonists for group 1 metabotropic receptors expressed in clonal RGT cell lines. Neuropharmacology 37:277–287.
Grieve, A., Dunlop, J., Schousboe, A., and Griffiths, R. 1991. Kinetic characterisation of excitatory sulphur amino acid transport in synaptosomes and in primary cultures of different brain cells. Biochem. Soc. Trans. 19:5S.
Griffiths, R., Grieve, A., Dunlop, J., Damgaard, I., Fosmark, H., and Schousboe, A. 1989. Inhibition by excitatory sulphur amino acids of the high-affinity L-glutamate transporter in synaptosomes and in primary cultures of cortical astrocytes and cerebellar neurons. Neurochem. Res. 14:333–343.
Dunlop, J., Grieve, A., Schousboe, A., and Griffiths, R. 1991. Stimulation of gamma-[3H]aminobutyric acid release from cultured mouse cerebral cortex neurons by sulphur-containing excitatory amino acid transmitter candidates: Receptor activation mediates two distinct mechanisms of release. J. Neurochem. 57:1388–1397.
Dunlop, J., Grieve, A., Damgaard, I., Schousboe, A., and Griffiths, R. 1992. Sulphur-containing excitatory amino acid-evoked Ca2+-independent release of D-[3H]aspartate from cultured cerebellar granule cells: The role of glutamate receptor activation coupled to reversal of the acidic amino acid plasma membrane carrier. Neuroscience 50:107–115.
Croucher, M. J., Thomas, L. S., Ahmadi, H., Lawrence, V., and Harris, J. R. 2001. Endogenous sulphur-containing amino acids: Potent agonists at presynaptic metabotropic glutamate auto-receptors in the rat central nervous system. Br. J. Pharmacol. 133:815–824.
Nicoletti, F. and Canonico, P. L. 1989. Glycine potentiates the stimulation of inositol phospholipid hydrolysis by excitatory amino acids in primary cultures of cerebellar neurons. J. Neurochem. 53:724–727.
Monaghan, D. T. and Cotman, C. W. 1986. Identification and properties of N-methyl-D-aspartate receptors in rat brain synaptic plasma membranes. Proc. Natl. Acad. Sci. USA 83:7532–7536.
Yang, J., McBride, S., Mak, D.-O.D., Vardi, N., Palczewski, K., Haeseleer, F., and Foskett, J. K. 2002. Identification of a family of calcium sensors as protein ligands of inositol trispho-sphate receptor Ca2+ release channels. Proc. Natl. Acad. Sci. USA 99:7711–7716.
Bootman, M. D., Berridge, M. J., and Roderick, H. L. 2002. Activating calcium release through inositol 1,4,5–trisphosphate receptors without inositol 1,4,5–trisphosphate. Proc. Natl. Acad. Sci. USA 99:7320–7322.
Fiskum, G., Murphy, A. N., and Beal, M. F. 1999. Mitochondria in neurodegeneration: Acute ischemia and chronic neurodegenerative diseases. J. Cereb. Blood Flow Metab. 19:351–369.
Murphy, A., Fiskum, G., and Beal, M. F. 1999. Mitochondria in neurodegeneration: Bioenergetic function in cell life and death. J. Cereb. Blood Flow Metab. 19:231–245.
Ankarcrona, M., Dypbukt, J. M., Bonfoco, E., Zhivotovsky, B., Orrenius, S., Lipton, S. A., and Nicotera, P. 1995. Glutamate-induced neuronal death: A succession of necrosis or apoptosis depending on mitochondrial function. Neuron 15: 961–973.
White, R. J. and Reynolds, I. J. 1996. Mitochondrial depolarization in glutamate-stimulated neurons: An early signal specific to excitotoxin exposure. J. Neurosci. 16:5688–5697.
Schinder, A. F., Olson, E. C., Spitzer, N. C., and Montal, M. 1996. Mitochondrial dysfunction is a primary event in glutamate neurotoxicity. J. Neurosci. 16:6125–6133.
Connern, C. P. and Halestrap, A. P. 1994. Recruitment of mitochondrial cyclophilin to the mitochondrial inner membrane under conditions of oxidative stress that enhance the opening of a calcium-sensitive non-specific channel. Biochem. J. 302: 321–324.
Yoshimoto, T. and Siejsö, B. K. 1999. Posttreatment with immunosuppressant cyclosporin A in transient focal ischemia. Brain Res. 839:283–291.
Snyder, S. H. and Sabatini, D. M. 1995. Immunophilins and the nervous system. Nature Med. 1:32–37.
Dingledine, R., Borges, K., Bowie, D., and Traynelis, S. F. 1999. The glutamate receptor ion channels. Pharmacol. Rev. 51:7–61.
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Lazarewicz, J.W., Ziembowicz, A., Matyja, E. et al. Homocysteine-Evoked 45Ca Release in the Rabbit Hippocampus Is Mediated by Both NMDA and Group I Metabotropic Glutamate Receptors: In Vivo Microdialysis Study. Neurochem Res 28, 259–269 (2003). https://doi.org/10.1023/A:1022329317218
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DOI: https://doi.org/10.1023/A:1022329317218