Skip to main content
PMC home page
CNS Drug Reviews logoLink to CNS Drug Reviews
. 2006 Jun 7;9(3):263–274. doi: 10.1111/j.1527-3458.2003.tb00253.x

Trialkylglycines: A New Family of Compounds with in Vivo Neuroprotective Activity

Ana M Sánchez‐Pérez 1, Carmina Montoliu 1, Vicente Felipo 1,✉
PMCID: PMC6741682  PMID: 14530798

ABSTRACT

Glutamate neurotoxicity is involved in the pathogenesis of neurodegenerative disorders such as Huntington's, Parkinson's and Alzheimer's diseases. It plays also a major role in the neuronal damage that occurs in brain ischemia and head trauma. Finding molecules that prevent or reverse glutamate neurotoxicity (excitotoxicity) is, therefore, of great interest. Strategies aimed at this end include the screening of libraries of compounds synthesized by combinatorial chemistry to find molecules that prevent neuronal death in vitro and in vivo. A library of trialkylglycines was screened to assess whether they prevent glutamate‐induced neuronal death in primary cultures of cerebellar neurons. Two types of trialkylglycines have been found that significantly reduce the incidence of glutamate‐induced neuronal death. The first type includes two compounds (referred to as 6–1–2 and 6–1–10) that efficiently prevent glutamate or NMDA‐induced neuronal death. They also prevent excitotoxicity in vivo as assessed by using two animal models of excitotoxicity: acute intoxication with ammonia and a model of cerebral ischemia in rats. Trialkylglycines 6–1–2 and 6–1–10 prevent ammonia‐induced (NMDA receptor‐mediated) death of mice and neuronal degeneration in the model of cerebral ischemia. The trialkylglycines of the second type act as open channel blockers of the NMDA receptor. The first group of trialkylglycines does not block NMDA receptor channels and does not affect the gluta‐mate‐nitric oxide‐cGMP pathway. Their molecular target has not yet been identified.

These two types of trialkylglycines (especially those that do not affect NMDA receptor function) might represent effective drugs for the treatment of neurodegeneration. They are likely to be well tolerated and have fewer side effects than NMDA receptor antagonists.

Keywords: Brain ischemia, Hepatic encephalopathy, Neurodegeneration, NMDA receptors, Trialkylglycines

Full Text

The Full Text of this article is available as a PDF (225.2 KB).

References

  • 1. Aarts M, Liu Y, Liu L, et al. Treatment of ischemic brain damage by perturbing NMDA receptor – PSD‐95 protein interactions. Science 2002;298:846–850. [DOI] [PubMed] [Google Scholar]
  • 2. Alberch J, Perez‐Navarro E, Canals J. Neuroprotection by neurotrophins and GDNF family members in the excitotoxic model of Huntington's disease. Brain Res Bull 2002;57:817–822. [DOI] [PubMed] [Google Scholar]
  • 3. Berman FW, Murray TF. Domoic acid neurotoxicity in cultured cerebellar granule neurons is mediated predominantly by NMDA receptors that are activated as a consequence of excitatory amino acid release. J Neurochem 1997;69:693–703. [DOI] [PubMed] [Google Scholar]
  • 4. Brauner‐Osborne H, Egebjerg J, Nielsen E, et al. Ligands for glutamate receptors: design and therapeutic prospects. J Med Chem 2000;43:2609–2645. [DOI] [PubMed] [Google Scholar]
  • 5. Chase TN, Oh JD. Striatal dopamine‐ and glutamate‐mediated dysregulation in experimental parkinsonism. Trends Neurosci 2000;23:S86–S91. [DOI] [PubMed] [Google Scholar]
  • 6. Choi DW. Calcium‐mediated neurotoxicity: Relationship to specific channel types and role in ischemic damage. Trends Neurosci 1988;11:465–469. [DOI] [PubMed] [Google Scholar]
  • 7. Choi DW. Ischemia‐induced neuronal apoptosis. Curr Opin Neurobiol 1996;6:667–672. [DOI] [PubMed] [Google Scholar]
  • 8. Dawson VL, Dawson TM, Bartley DA, et al. Mechanisms of nitric oxide‐mediated neurotoxicity in primary brain cultures. J Neurosci 1993;13:2651–2661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Debonnel G, de Montigny C, Beauchesne L. Domoic acid, the alleged “mussel toxin”, might produce its neurotoxic effect through kainate receptor activation: An electrophysiological study in the dorsal hippocampus. Can J Physiol Pharmacol 1989;67:29–33. [DOI] [PubMed] [Google Scholar]
  • 10. Felipo V, Miñana M‐D, Grisolía S. Inhibitors of protein kinase C prevent the toxicity of glutamate in primary neuronal cultures. Brain Res 1993;604:192–196. [DOI] [PubMed] [Google Scholar]
  • 11. Ferrermontiel AV, Merino JM, Planellscases R, Sun W, Montal M. Structural determinants of the blocker binding site in glutamate and NMDA receptor channels. Neuropharmacology 1998;37:139–147. [DOI] [PubMed] [Google Scholar]
  • 12. Figliozzi G, Goldsmith R, Ng S, et al. Synthesis of N‐substituted glycine peptoid libraries. Meth Enzymol 2001;267:437–447. [DOI] [PubMed] [Google Scholar]
  • 13. Garcia‐Martinez C, Humet M, Planells‐Cases R, et al. Attenuation of thermal nociception and hyperalgesia by VR1 blockers. Proc Natl Acad Sci USA 2002;99:2374–2379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Hermenegildo C, Monfort P, Felipo V. Activation of N‐methyl‐D‐aspartate receptors in rat brain in vivo following acute ammonia intoxication: Characterization by in vivo brain microdialysis. Hepatology 2000;31:709–715. [DOI] [PubMed] [Google Scholar]
  • 15. Hermenegildo C, Marcaida G, Montoliu C, et al. NMDA receptor antagonists prevent acute ammonia toxicity in mice. Neurochem Res 1996;21:1237–1244. [DOI] [PubMed] [Google Scholar]
  • 16. Hermenegildo C, Montoliu C, Llansola M, et al. Chronic hyperammonemia impairs the glutamate‐nitric oxide‐cyclic GMP pathway in cerebellar neurons in culture and in the rat in vivo. Eur J Neurosci 1998;10:3201–3209. [DOI] [PubMed] [Google Scholar]
  • 17. Hermenegildo C, Saez R, Minoia C, et al. Chronic exposure to aluminium impairs the glutamate‐nitric oxide‐cyclic GMP pathway in the rat in vivo. Neurochem Int 1999;34:245–253. [DOI] [PubMed] [Google Scholar]
  • 18. Ikonomidou C, Stefovska V, Turski L. Neuronal death enhanced by N‐methyl‐D‐aspartate antagonists. Proc Natl Acad Sci USA 2000;97:12885–12890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Kothakota S, Azuma T, Reinhard C, et al. Caspase‐3‐generated fragment of gelsolin: Effector of morphological change in apoptosis. Science 1997;278:294–298. [DOI] [PubMed] [Google Scholar]
  • 20. Lafon‐Cazal M, Culcasi M, Gaven F, et al. Nitric oxide, superoxide and peroxynitrite: Putative mediators of NMDA‐induced cell death in cerebellar granule cells. Neuropharmacology 1993;32:1259–1266. [DOI] [PubMed] [Google Scholar]
  • 21. Lipton SA. Prospects for clinically tolerated NMDA antagonists — Open‐channel blockers and alternative redox states of nitric oxide. Trends Neurosci 1993;16:527–532. [DOI] [PubMed] [Google Scholar]
  • 22. Montoliu C, Llansolam M, Kosenko E, et al. Role of cyclic GMP in glutamate neurotoxicity in primary cultures of cerebellar granule cells. Neuropharmacology 1999;38:1883–1891. [DOI] [PubMed] [Google Scholar]
  • 23. Montoliu C, Humet M, Canales JJ, et al. Prevention of in vivo excitotoxicity by a family of trialkylglycines, a novel class of neuroprotectants. J Pharmacol Exp Ther 2002;301:29–36. [DOI] [PubMed] [Google Scholar]
  • 24. Newcomer J, Krystal J. NMDA receptor regulation of memory and behavior in humans. Hippocampus 2001;11:529–549. [DOI] [PubMed] [Google Scholar]
  • 25. Nicotera P, Leist M. Excitotoxicity. Cell Death Diff 1997;4:517–518. [DOI] [PubMed] [Google Scholar]
  • 26. Parsons CG, Danysz W, Quack G. Memantine is a clinically well tolerated N‐methyl‐D‐aspartate (NMDA) receptor antagonist — a review of preclinical data. Neuropharmacology 1999;38:735–767. [DOI] [PubMed] [Google Scholar]
  • 27. Planellscases R, Montoliu C, Humet M, et al. A novel N‐methyl‐D‐aspartate receptor open channel blocker with in vivo neuroprotectant activity. J Pharmacol Exp Ther 2002;302:163–173. [DOI] [PubMed] [Google Scholar]
  • 28. Pulsinelli W, Brierley JB. Anew model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke 1979;10:267–272. [DOI] [PubMed] [Google Scholar]
  • 29. Schinder AF, Olson EC, Spitzer NC, Montal M. Mitochondrial dysfunction is a primary event in glutamate neurotoxicity. J Neurosci 1996;16:6125–6133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Snyder SH. No NO prevents parkinsonism. Nat Med 2003;2:965–966. [DOI] [PubMed] [Google Scholar]
  • 31. Strijbos PJ. Nitric oxide in cerebral ischemic neurodegeneration and excitotoxicity. Crit Rev Neurobiol 1998;12:223–243. [DOI] [PubMed] [Google Scholar]
  • 32. Zeron M, Hansson O, Chen N, et al. Increased sensitivity to N‐methyl‐D‐aspartate receptor‐mediated excitotoxicity in a mouse model of Huntington's disease. Neuron 2002;33:849–860. [DOI] [PubMed] [Google Scholar]

Articles from CNS Drug Reviews are provided here courtesy of Wiley

RESOURCES