Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1991 Nov;104(3):760–764. doi: 10.1111/j.1476-5381.1991.tb12501.x

Effects of the glycine prodrug milacemide (2-N-pentylaminoacetamide) on catecholamine secretion from isolated adrenal medulla chromaffin cells.

G Yadid 1, O Zinder 1, M B Youdim 1
PMCID: PMC1908222  PMID: 1797336

Abstract

1. Milacemide (2-n-pentylaminoacetamide) is a glycine prodrug which readily crosses the blood brain barrier and increases brain glycine and glycineamide. In vitro and in vivo studies, with numerous tissues, including adrenal chromaffin cells, have clearly shown that the formation of the latter metabolites is exclusively mediated by monoamine oxidase B for which milacemide is a substrate. 2. Milacemide, glycineamide and glycine caused a time- and dose-dependent release of catecholamines from bovine isolated chromaffin cells. 3. Milacemide (10(-4) M) induced catecholamine release was roughly 30% of that initiated by acetylcholine (10(-4) M), the natural secretagogue. 4. The combined effects of milacemide (10(-4) M) and acetycholine (10(-4) M) on catecholamine secretion from chromaffin cells is additive, suggesting that milacemide does not act through the normal nicotinic receptor release mechanism. 5. The release of catecholamines from chromaffin cells in response to milacemide (10(-4) M) was partially inhibited by the selective MAO-B inhibitors (-)-deprenyl (10(-7) M) and AGN 1135 (10(-6) M). This indicates that the MAO-B derived metabolites, glycineamide and glycine, contribute to the secretion of catecholamines as does milacemide itself. 6. It is apparent that release of catecholamines by glycine is mediated by its uptake into the cells since [3H]-glycine uptake and catecholamine release showed a highly significant correlation (r = 0.96).

Full text

PDF
760

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bormann J., Clapham D. E. gamma-Aminobutyric acid receptor channels in adrenal chromaffin cells: a patch-clamp study. Proc Natl Acad Sci U S A. 1985 Apr;82(7):2168–2172. doi: 10.1073/pnas.82.7.2168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  3. Curtis D. R., Duggan A. W., Johnston G. A. The specificity of strychnine as a glycine antagonist in the mammalian spinal cord. Exp Brain Res. 1971 Jun 29;12(5):547–565. doi: 10.1007/BF00234248. [DOI] [PubMed] [Google Scholar]
  4. Davidoff R. A., Adair R. GABA and glycine transport in frog CNS: high affinity uptake and potassium-evoked release in vitro. Brain Res. 1976 Dec 24;118(3):403–415. doi: 10.1016/0006-8993(76)90308-5. [DOI] [PubMed] [Google Scholar]
  5. Greenberg A., Zinder O. Alpha- and beta-receptor control of catecholamine secretion from isolated adrenal medulla cells. Cell Tissue Res. 1982;226(3):655–665. doi: 10.1007/BF00214792. [DOI] [PubMed] [Google Scholar]
  6. Grenningloh G., Rienitz A., Schmitt B., Methfessel C., Zensen M., Beyreuther K., Gundelfinger E. D., Betz H. The strychnine-binding subunit of the glycine receptor shows homology with nicotinic acetylcholine receptors. Nature. 1987 Jul 16;328(6127):215–220. doi: 10.1038/328215a0. [DOI] [PubMed] [Google Scholar]
  7. Hannuniemi R., Oja S. S. Uptake of leucine, lysine, aspartic acid, and glycine into isolated neurons and astrocytes. Neurochem Res. 1981 Aug;6(8):873–884. doi: 10.1007/BF00965045. [DOI] [PubMed] [Google Scholar]
  8. Hardy J. A., Barton A., Lofdahl E., Cheetham S. C., Johnston G. A., Dodd P. R. Uptake of gamma-aminobutyric acid and glycine by synaptosomes from postmortem human brain. J Neurochem. 1986 Aug;47(2):460–467. doi: 10.1111/j.1471-4159.1986.tb04523.x. [DOI] [PubMed] [Google Scholar]
  9. Hiram Y., Nir A., Greenberg A., Zinder O. Temperature effects in the stimulus-secretion process from isolated chromaffin cells. Biophys J. 1984 Apr;45(4):651–658. doi: 10.1016/S0006-3495(84)84206-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Houtkooper M. A., van Oorschot C. A., Rentmeester T. W., Höppener P. J., Onkelinx C. Double-blind study of milacemide in hospitalized therapy-resistant patients with epilepsy. Epilepsia. 1986 May-Jun;27(3):255–262. doi: 10.1111/j.1528-1157.1986.tb03537.x. [DOI] [PubMed] [Google Scholar]
  11. Janssens de Varebeke P., Cavalier R., David-Remacle M., Youdim M. B. Formation of the neurotransmitter glycine from the anticonvulsant milacemide is mediated by brain monoamine oxidase B. J Neurochem. 1988 Apr;50(4):1011–1016. doi: 10.1111/j.1471-4159.1988.tb10566.x. [DOI] [PubMed] [Google Scholar]
  12. Janssens de Varebeke P., Pauwels G., Buyse C., David-Remacle M., De Mey J., Roba J., Youdim M. B. The novel neuropsychotropic agent milacemide is a specific enzyme-activated inhibitor of brain monoamine oxidase B. J Neurochem. 1989 Oct;53(4):1109–1116. doi: 10.1111/j.1471-4159.1989.tb07403.x. [DOI] [PubMed] [Google Scholar]
  13. Kalir A., Sabbagh A., Youdim M. B. Selective acetylenic 'suicide' and reversible inhibitors of monoamine oxidase types A and B. Br J Pharmacol. 1981 May;73(1):55–64. doi: 10.1111/j.1476-5381.1981.tb16771.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kataoka Y., Fujimoto M., Alho H., Guidotti A., Geffard M., Kelly G. D., Hanbauer I. Intrinsic gamma aminobutyric acid receptors modulate the release of catecholamine from canine adrenal gland in situ. J Pharmacol Exp Ther. 1986 Nov;239(2):584–590. [PubMed] [Google Scholar]
  15. Kitayama S., Koyama Y., Morita K., Dohi T., Tsujimoto A. Increase in catecholamine release and 45Ca2+ uptake induced by GABA in cultured bovine adrenal chromaffin cells. Eur J Pharmacol. 1986 Nov 12;131(1):145–147. doi: 10.1016/0014-2999(86)90529-7. [DOI] [PubMed] [Google Scholar]
  16. Livett B. G. Adrenal medullary chromaffin cells in vitro. Physiol Rev. 1984 Oct;64(4):1103–1161. doi: 10.1152/physrev.1984.64.4.1103. [DOI] [PubMed] [Google Scholar]
  17. Livett B. G., Boksa P. Receptors and receptor modulation in cultured chromaffin cells. Can J Physiol Pharmacol. 1984 Apr;62(4):467–476. doi: 10.1139/y84-076. [DOI] [PubMed] [Google Scholar]
  18. Logan W. J., Snyder S. H. High affinity uptake systems for glycine, glutamic and aspaspartic acids in synaptosomes of rat central nervous tissues. Brain Res. 1972 Jul 20;42(2):413–431. doi: 10.1016/0006-8993(72)90540-9. [DOI] [PubMed] [Google Scholar]
  19. Mangano T. J., Patel J., Salama A. I., Keith R. A. Glycine-evoked neurotransmitter release from rat hippocampal brain slices: evidence for the involvement of glutaminergic transmission. J Pharmacol Exp Ther. 1990 Feb;252(2):574–580. [PubMed] [Google Scholar]
  20. Marley P. D. Desensitization of the nicotinic secretory response of adrenal chromaffin cells. Trends Pharmacol Sci. 1988 Mar;9(3):102–107. doi: 10.1016/0165-6147(88)90177-0. [DOI] [PubMed] [Google Scholar]
  21. Saletu B., Anderer P., Kinsperger K., Grünberger J. Topographic brain mapping of EEG in neuropsychopharmacology--Part II. Clinical applications (pharmaco EEG imaging). Methods Find Exp Clin Pharmacol. 1987 Jun;9(6):385–408. [PubMed] [Google Scholar]
  22. Saletu B., Grünberger J., Linzmayer L. Acute and subacute CNS effects of milacemide in elderly people: double-blind, placebo-controlled quantitative EEG and psychometric investigations. Arch Gerontol Geriatr. 1986 Oct;5(3):165–181. doi: 10.1016/0167-4943(86)90019-1. [DOI] [PubMed] [Google Scholar]
  23. Schmidt C. J., Taylor V. L. Strychnine-sensitive, glycine-induced release of [3H]norepinephrine from rat hippocampal slices. J Neurochem. 1990 Jun;54(6):2077–2081. doi: 10.1111/j.1471-4159.1990.tb04913.x. [DOI] [PubMed] [Google Scholar]
  24. Siemers E. R., Rea M. A., Felten D. L., Aprison M. H. Distribution and uptake of glycine, glutamate and gamma-aminobutyric acid in the vagal nuclei and eight other regions of the rat medulla oblongata. Neurochem Res. 1982 Apr;7(4):455–468. doi: 10.1007/BF00965497. [DOI] [PubMed] [Google Scholar]
  25. Tauck D. L., Frosch M. P., Lipton S. A. Characterization of GABA- and glycine-induced currents of solitary rodent retinal ganglion cells in culture. Neuroscience. 1988 Oct;27(1):193–203. doi: 10.1016/0306-4522(88)90230-8. [DOI] [PubMed] [Google Scholar]
  26. VON EULER U. S., FLODING I. A fluorimetric micromethod for differential estimation of adrenaline and noradrenaline. Acta Physiol Scand Suppl. 1955;33(118):45–56. [PubMed] [Google Scholar]
  27. Yadid G., Youdim M. B., Zinder O. High-affinity strychnine binding to adrenal medulla chromaffin cell membranes. Eur J Pharmacol. 1990 Jan 17;175(3):365–366. doi: 10.1016/0014-2999(90)90579-u. [DOI] [PubMed] [Google Scholar]
  28. Youdim M. B., Kerem D., Duvdevani Y. The glycine-prodrug, milacemide, increases the seizure threshold due to hyperbaric oxygen; prevention by 1-deprenyl. Eur J Pharmacol. 1988 Jun 10;150(3):381–384. doi: 10.1016/0014-2999(88)90023-4. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES