Advertisement

Agents and Actions

, Volume 1, Issue 1, pp 9–13 | Cite as

Homocysteine-induced convulsions in the rat: Protection by homoserine, serine, betaine, glycine and glucose

  • Herbert Sprince
  • Clarence M. Parker
  • Joseph A. JosephsJr.
Research Reports

Abstract

Intraperitoneal injection into rats of 5.5 mM/kg ofdl-homocysteine (free base) ordl-homocysteine thiolactone · HCl resulted in violent convulsions (approx. 50%) and some fatalities (approx. 15%), following a short, initial period of depressant activity. Metabolically related metabolites (viz. methionine, serine, homoserine, cysteine and homocystine) showed no convulsant activity and virtually no lethal effects at doses as high as 7.4 mM/kg. At 7.4 mM/kg, homocysteine and its lactone resulted in 95% convulsions and 90% fatalities. These obervations point to a structural factor for convulsant activity indl-homocysteine not found in the related methionine metabolites tested. The half-maximal convulsant dose (CD50) was 750 (698–806) mg/kg and the half-maximal lethal dose (LD50) was 840 (794–889) mg/kg, both values having Litchfield-Wilcoxon confidence limits of 19/20. Prior intraperitineal injection of large doses (14.8 mM/kg) of homoserine, serine, betaine, glycine and glucose protected against convulsions and death induced by the CD50 dose (i.e. 750 mg/kg) ofdl-homocysteine. Our findings indicate that, of all the major metabolites of methionine tested, homocysteine would seem to be the only one which is epileptogenic and the most toxic (to the point of lethality).

Keywords

Glycine Cysteine Serine Methionine Homocysteine 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. [1]
    H. Sprince, J. A. Josephs, jr. andC. R. Wilpizeski,Neuropharmacological Effects of 1,4-Butanediol and Related Congeners Compared with Those of Gamma-Hydroxybutyrate and Gamma-Butyrolactone, Life Sci.5, 2041–2052 (1966).CrossRefGoogle Scholar
  2. [2]
    G. Ungar andD. V. Romano,Sulfhydryl Groups in Resting and Stimulated Rat Brain; Their Relationship with Protein Structure, Proc. Soc. Exptl Biol. Med.97, 324–326 (1958).Google Scholar
  3. [3]
    V. V. Portugalov, E. L. Dovedova andV. G. Skrebitsky,On Some Mechanisms Regulating the Chemical Activity of the Neuron Mitochondria, J. Histochem. Cytochem.10, 213–221 (1962).Google Scholar
  4. [4]
    W. Pollin, P. V. Cardon, Jr. andS. S. Kety,Effects of Amino Acid Feedings in Schizophrenic Patients Treated with Iproniazid, Science133, 104–105 (1961).PubMedGoogle Scholar
  5. [5]
    G. G. Brune andH. E. Himwich,Effects of Methionine Loading on the Behavior of Schizophrenic Patients, J. Nerv. Ment. Dis.134, 447–450 (1962).PubMedGoogle Scholar
  6. [6]
    F. Alexander, G. C. Curtis III, H. Sprince andA. P. Crosley,L-Methionine and L-Tryptophan Feedings in Non-Psychotic and Schizophrenic Patients with and without Tranylcypromine, J. Nerv. Ment. Dis.137, 135–142 (1963).PubMedGoogle Scholar
  7. [7]
    G. G. Haydu, A. Dhrymiotis, C. Korenyi andL. Goldschmidt,Effects of Methionine and Hydroxychloroquine in Schizophrenia, Am. J. Psychiat.122, 560–564 (1965).PubMedGoogle Scholar
  8. [8]
    G. G. Brune,Tryptophan Metabolism in Psychoses, inAmines and Schizophrenia (Ed. H. E. Himwich, S. S. Kety and J. R. Smythies, Pergamon Press, New York 1967), p. 87–96.Google Scholar
  9. [9]
    A. J. Friedhoff andE. van Winkle,New Developments in the Investigation of the Relationship of 3,4-Dimethoxyphenylethylamine to Schizophrenia, inAmines and Schizophrenia (Ed. H. E. Himwich, S. S. Kety and J. R. Smythies, Pergamon Press, New York 1967), p. 19–21.Google Scholar
  10. [10]
    T. L. Perry, S. Hansen, L. MacDougall andP. D. Warrington,Sulfur-Containing Amino Acids in the Plasma and Urine of Homocystinurics, Clin. Chim. Acta15, 409–420 (1960).CrossRefGoogle Scholar
  11. [11]
    J. A. Wada andH. Ikeda,The Susceptibility to Auditory Stimuli of Animals Treated with Methionine Sulfoximine, Exptl Neurology15, 157–165 (1966).CrossRefGoogle Scholar
  12. [12]
    E. H. Jenney andC. C. Pfeiffer,The Convulsant Effect of Hydrazides and the Antidotal Effect of Anticonvulsants and Metabolites, J. Pharmac. Exptl Ther.122, 110–123 (1958).Google Scholar
  13. [13]
    M. A. Medina,The In Vivo Effects of Hydrazines and Vitamin B 6 on the Metabolism of Gamma-Aminobutyric Acid, J. Pharmac. Exptl Ther.140, 133–137 (1963).Google Scholar
  14. [14]
    A. Meister,Biochemistry of the Amino Acids, 2nd ed., vol. 1 (Academic Press, New York, N.Y. 1964), p. 221.Google Scholar
  15. [15]
    J. T. Litchfield jr. andF. Wilcoxon,A Simplified Method of Evaluating Dose-Effect Experiments, J. Pharmac. and Exptl Ther.96, 99–113 (1949).Google Scholar
  16. [16]
    V. DuVigneaud,A Trail of Research in Sulfur Chemistry and Metabolism (Cornell University Press, Ithaca, N.Y. 1952), p. 89–125.Google Scholar
  17. [17]
    J. S. Roth andJ. B. Allison,The Effects of Feeding Excess dl-Methionine and Choline Chloride to Rats on a Casein Diet, J. Biol. Chem.183, 173–178 (1950).Google Scholar
  18. [18]
    H. P. Cohen, H. C. Choitz andC. P. Berg,Response of Rats to Diets High in Methionine and Related Compounds, J. Nutrition64, 555–569 (1958).Google Scholar
  19. [19]
    H. Sprince,Metabolic Interrelationships of Tryptophan and Methionine in Relation to Mental Illness, inAmines and Schizophrenia (Ed. H. E. Himwich, S. S. Kety and J. R. Smythies, Pergamon Press, New York 1967), p. 97–114.Google Scholar

Copyright information

© Birkhäuser-Verlag 1969

Authors and Affiliations

  • Herbert Sprince
    • 1
    • 2
  • Clarence M. Parker
    • 1
    • 2
  • Joseph A. JosephsJr.
    • 1
    • 2
  1. 1.U.S. Veterans Administration HospitalCoatesvilleUSA
  2. 2.The Departments of Psychiatry and PharmacologyJefferson Medical College and Medical CenterPhiladelphiaUSA

Personalised recommendations