Homocysteic Acid, an Endogenous Agonist of NMDA-Receptor: Release, Neuroactivity and Localization

  • M. Cuénod
  • K. Q. Do
  • P. L. Herrling
  • W. A. Turski
  • C. Matute
  • P. Streit
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 203)


Many lines of evidence are pointing toward a role of the excitatory amino acid transmitters and their receptors in the mechanisms leading to epileptic seizure disorders. Various excitatory amino acids and structural analogs, such as kainic acid, quinolinic acid or ibotenic acid, initiate epilepticlike discharges when applied to nervous tissue (Ben-Ari et al.,1979; French et al.,1982; Schwarcz et al., 1984). Changes in excitatory amino acid content in cerebral tissue and cerebrospinal fluid have been reported to occur in various animal models and human epileptic conditions (Van Gelder et al., 1972; Morselli et al., 1981).Most convincing are the potent anticonvulsanteffects of D-2-amino-7-phosphonoheptanoic acid (AP-7), a specific N-methyl-D-aspartic acid (NMDA) receptor antagonist, in several animal models of epilepsy (Croucher et al.,1982; Meldrum et al., 1983).


High Pressure Liquid Chromatography Excitatory Amino Acid Kainic Acid Quinolinic Acid Cysteic Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Baba, A., Yamagami, S., Mizuo, H., and Iwata, H., 1980, Microassay of cysteine sulfinic acid by an enzymatic cycling method, Anal. Biochem. 101:288.Google Scholar
  2. Baba, A., Okumura, S., Mizuo, H., and Iwata, H., 1983, Inhibition by diazepam and y-aminobutyric acid Qf depolarization-induced release of [14C] cysteine sulfinate and [H]glutamate in rat hippocampal slices,J. Neurochem. 40:280.Google Scholar
  3. Baudry, M., Kramer, K., Fagni, L., Recasens, M., and Lynch, G., 1983, Classification and properties of acidic amino acid receptors in hippocampus, Mol. Pharmacol. 24:222.Google Scholar
  4. Ben-Ari, Y., Lagowska, J., Tremblay, E., and Le Gal La Salle G., 1979, A new model of focal status epilepticus: intraamygdaloid application of kainic acid elicits repetitive secondarily generalized convulsive seizures, Brain Res. 163: 176.Google Scholar
  5. Chang, J.-Y, 1981, Isolation and characterization of polypeptide at the picomole level, Biochem. J. 199:537.Google Scholar
  6. Collingridge, G.L., Kehl, S.J., and McLennan, H., 1983, Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus, J. Physiol. 334:33.Google Scholar
  7. Cox, D.W.G., Headley, M.H., and Watkins, J.C., 1977, Actions of L- and D-homocysteate in rat CNS: a correlation between low-affinity uptake and the time courses of excitation by microelectrophoretically applied L-glutamate analogues, J. Neurochem. 29:579.Google Scholar
  8. Croucher, M.J., Collins, J.F., and Meldrum, B.S., 1982, Anticonvulsant action of excitatory amino acid antagonist, Science 216: 899.Google Scholar
  9. Cuénod, M., Bagnoli, P., Beaudet, A., Rustioni, A., Wiklund, L., and Streit, P., 1982, Transmitter specific retrograde labeling of neurons,in: Cytochemical Methods in Neuroanatomv V. Chan-Palay and S. L. Palay,Alan R. Liss, Inc., New York, P. 17.Google Scholar
  10. Cuénod, M., and Streit, P., 1983, Neuronal tracing using retrograde migration of labeled transmitter-related compounds, in: Methods in Chemical. Neuroanatomv A. Björklund and T. Hökfelt,Elsevier, Amsterdam,p. 365.Google Scholar
  11. Cuénod, M., Do, K.Q., Matute, C., and Streit, P., 1986, Identification of pathways for acidic amino acid transmitters and search for new candidates: sulphur containing amino acids, in: Excitatory Amino Acids P.J. Roberts, J. Storm-Mathisen and H.F. Bradford,Macmillan Press, London, in press.Google Scholar
  12. Curtis, D.R., and Watkins, J.C., 1960, The excitation and depression of spinal neurones by structurally related amino acids, J. Neurochem. 6:117.Google Scholar
  13. Dempsey, E.W., and Morison, R.S., 1942a, The production of rhythmically recurrent cortical potentials after localized thalamic stimulation, Amer. J. Phvsiol. 135:293.Google Scholar
  14. Dempsey, E.W., and Morison, R.S., 1942b, The interaction of certain spontaneous and induced cortical potentials, Amer. J. Physiol. 135:301.Google Scholar
  15. Do, K.Q., Mattenberger, M., Streit, P., and Cuênod, M. 1986a, In vitro release of endogenous excitatory sulphur containing amino acids from various rat brain regions, J, Neurochem. 46:779.Google Scholar
  16. Do, K.Q., Herrling, P.L., Streit, P., Turski, W.A., and Cuénod, M. 1986b, In vitro release and electrophysiological effects in situ of homocysteic acid, an endogenous N-methyl-D-aspartic acid agonist, inthe mammalian striatum, J. Neurosci. in press.Google Scholar
  17. Evans, R.H., Francis, A.A., Jones, A.W., Smith, D.A.S., and Watkins, J.C., 1982, The effects of a series of omegaphosphonic alpha-carboxylic amino acid-induced responses in the isolated spinal cord preparation, Br. J, Pharmac. 75:65.Google Scholar
  18. Fonnum, F., Ureide, A., Kvale, I., Walker, J., and Walaas, I., 1981, Glutamate in cortical fibers, in: Glutamate as a Neurotransmitter G. DiChiara and G.L. Gessa,Raven Press, New York, p. 29.Google Scholar
  19. French, E.D, Aldinio, C., and Schwarcz, R., 1982, Intrahippocampal kainic acid, seizures and local neuronal degeneration: relationships assessed in unanesthetized rats, Neuroscience 7: 2525.Google Scholar
  20. Hanberry, J., and Jasper, H.H., 1953, Independence of diffuse thalamic projection system shown by specific nuclear destructions, J. Neurophysiol. 16:252.Google Scholar
  21. Harris, E.W., Ganong, A.H., and Cotman, C.W., 1984, Long-term potentiation in the hippocampus involves activation of N-methyl-D-aspartate receptors, Brain Res t323: 132.Google Scholar
  22. Herkenham, M., 1980, Laminar organization of thalamic projections to the rat cortex, Science 207: 532.Google Scholar
  23. Herrling, P.L., Morris, R., and Salt, T.E., 1983, Effects of excitatory amino acids and their antagonists on membrane and action potentials of cat caudate neurones, J, Phvsiol. 339:207.Google Scholar
  24. Herrling, P.L., 1985, Pharmacology of the corticocaudate excitatory post-synaptic potential in the cat: evidence for its mediation by quisqualate- or kainate-receptors, Neuroscience 14:417.Google Scholar
  25. Herrling, P.L., and Turski, W.A., 1986 Interactions of sulphur-containing excitatory amino acids with membrane and synaptic potentials of cat caudate neurons, in: Excitatory Amino Acids P.J. Roberts, J. StormMathisen and H.F. Bradford,Macmillan Press, London, in press.Google Scholar
  26. Ida, S., and Kuriyama, K., 1983, Simultaneous determination of cysteine sulfinic acid and cysteic acid in rat brain by high-performance liquid chromatography, Anal. Biochem. 130:95.Google Scholar
  27. Iwata, H., Yamagami, S., Mizuo, H., and Baba, H., 1982, Cysteine sulfinic acid in the central nervous system: uptake and release of cysteine sulfinic acid by a rat brain preparation, J. Neurochem. 38:1268.Google Scholar
  28. Jasper, H.H., 1960, Unspecific thalamocortical relations, in: Handbook of Physiology: Neurophysiology J. Field, H.W. Magoun and V.E. Hall,American Physiological Society, Washington, p. 1307.Google Scholar
  29. Lambert, J.D.C., Flatman, J.A., and Engberg, I., 1981, Actions of excitatory amino acids on membrane conductance and potential in motoneurones,in: Glutamate as a Neurotransmitter G. DiChiara and G.L. Gessa,Raven Press, New York, p. 205.Google Scholar
  30. Luini, A., Goldberg, O., and Teichberg, V.I., 1984, An evaluation of selected brain constituants as putative excitatory neurotransmitters, Brain Res., 324: 271.Google Scholar
  31. Mayer, M.L., and Westbrook, G.L., 1984, Mixed-agonist action of excitatory amino acids on mouse spinal cord neurones under voltage clamp,J. Physiol. 354:29.Google Scholar
  32. Mayer, M.L., and Westbrook, G.L., 1985, The action of N-methyl-D-aspartic acid on mouse spinal neurones in culture, J. Physiol. 361:65.Google Scholar
  33. Meldrum, B.S., Croucher, M.J., Badman, G., and Collins, J.F., 1983, Anti-epileptic action of excitatory amino acid antagonists in photosensitive baboon, Papio papio, Neurosci. Lett. 39:101.Google Scholar
  34. Mewett, K.N., Oakes, D.J., Olverman, H.J., Smith, D.A.S., and Watkins, J.C., 1983, Pharmacology of the excitatory actions of sulphonic and sulphinic amino acids, in: CNS Receptors - From Molecular Pharmacology to Behavior P. Mandel and F.V. DeFeudis,Raven Press, New York, p. 163.Google Scholar
  35. Monaghan, D.T., mnd Cotman, C.W., 1985, Distribution of N-methyl-D-aspartate- sensitive L-(H]Glutamate-binding sites in rat brain, J. press.Google Scholar
  36. Morison, R.S., and Dempsey, E.W., 1942, A study of thalamo-cortical relations, Amer. J. Physiol. 135:281.Google Scholar
  37. Morselli, P.L., Lloyd, K.G., Löscher, W., Meldrum, B., and Reynolds, E.H., 1981, Neurotransmitters, Seizures and Epilepsy Raven Press,New York.Google Scholar
  38. Mudd, S.H., and Levy, H.L., 1983, Disorders of transsulfuration, in: The Metabolic Basis of Inherited Diseases J.B. Stanbury, J.B. Wyngaarden, D.S. Fredrickson, J.L. Goldstein and M.S. Brown,McGraw-Hill, New York, p. 522.Google Scholar
  39. Ottersen, O.P., Fisher, B.O., and Storm-Mathisen, J., 1983, Retrograde transport of D-[H]aspartate in thalamo-cortical neurones, Neurosci. Lett. 42:19.Google Scholar
  40. Perkins, M.N., Collins, J.F., and Stone, T.W., 1982, Isomeres of 2-amino-7phosphonoheptanoic acid as antagonists of neural excitants, Neurosci. Lett. 32:65.Google Scholar
  41. Purpura, D.P., 1959, Nature of electrocortical potentials and synaptic organizations in cerebral and cerebellar cortex, in: International Review of Neurobiology C.C. Pfeiffer and J.R. Smythies,Academic Press, New York, p. 47.Google Scholar
  42. Purpura, D.P., and Shofer, R.J., 1964, Cortical intracellular potentials during augmenting and recruiting responses. I. Effects of injected hyperpolarizing currents on evoked membrane potential changes,J. Neurophvsiol. 27:117.Google Scholar
  43. Purpura, D.P., Shofer, R.J., and Musgrave, F.S., 1964, Cortical intracellular potentials during augmenting and recruiting responses. H. Patterns of synaptic activities in pyramidal and nonpyramidal tract neurons, J. Neurophvsiol. 27:133.Google Scholar
  44. Recasens, M., Varga, V., Nanopoulos, D., Saadoun, F., Vincendon, G., and Benavides, J., 1982, Evidence for cysteine sulfinate as a neurotransmitter, Brain Res. 239: 153.Google Scholar
  45. Recasens, M., Saadoun, F., Varga, V., DeFeudis, F.V., Mandel, P., Lynch, G., and Vincendon, G., 1983, Separate binding sites in rat brain synaptic membranes for L-cysteine sulfinate and L-glutamate, Neurochem. Int. 5:89.Google Scholar
  46. Recasens, M., Fagni, L., Bamdry, M., and Lynch, G., 1984. Potassium and veratrine-stimulated L-[H]cysteine sulfinate and L-[H]glutamate release from rat brain slices, Neurochem. Int. 6:325.Google Scholar
  47. Schwarcz, R., Foster, A.C., French, E.D., Whetsell, W.O. Jr., and Köhler, C., 1984, Excitotoxic models for neurodegenerative disorders, Life Sci. 35: 19.PubMedCrossRefGoogle Scholar
  48. Storm-Mathisen, J., Leknes, A.K., Bore, A.T., Vaaland, J.L., Edminson, P., Haug, F.-M.S., and Ottersen, 0.P., 1983, First visualization of glutamate and GABA in neurones by immunocytochemistry, Nature 301: 517.Google Scholar
  49. Streit, P., 1980, Selective retrograde labeling indicating the transmitter of neuronal pathways, J. Comp. Neurol. 191:429.Google Scholar
  50. Streit, P., 1984, Glutamate and aspartate as transmitter candidates for systems of the cerebral cortex, in: Cerebral Cortex Vol. 2 E.G. Jones and A. Peters,Plenum Publ. Corp., New York, p. 119.Google Scholar
  51. Van Gelder, N.M., Sherwin, A.L., and Rasmussen, T., 1972, Amino acid content of epileptogenic human brain. Focal versus surrounding regions,Brain Res. 40: 385.Google Scholar
  52. Watkins, J.C., and Evans, R.H., 1981, Excitatory amino acid transmitters, Ann. Rev. Pharmacol. Toxicol. 21:165.Google Scholar
  53. Wu, S.M., and Dowling, J.E., 1978, L-aspartate: evidence for a role in cone photoreceptor synaptic transmission in the carp retina, Proc. Natl, Acad. Sci. USA 75:5205.Google Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • M. Cuénod
    • 1
  • K. Q. Do
    • 1
  • P. L. Herrling
    • 2
  • W. A. Turski
    • 2
  • C. Matute
    • 1
  • P. Streit
    • 1
  1. 1.Brain Research InstituteUniversity of ZürichZürichSwitzerland
  2. 2.Wander Research Institute (a Sandoz Research Unit)BernSwitzerland

Personalised recommendations