Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 368, Issue 6, pp 538–545 | Cite as

AMPA-receptor activation is involved in the antiamnesic effect of DM 232 (unifiram) and DM 235 (sunifiram)

  • N. Galeotti
  • C. Ghelardini
  • A. Pittaluga
  • A. M. Pugliese
  • A. Bartolini
  • D. Manetti
  • M. N. Romanelli
  • F. Gualtieri
Original Article

Abstract

DM 232 and DM 235 are novel antiamnesic compounds structurally related to ampakines. The involvement of AMPA receptors in the mechanism of action of DM 232 and DM 235 was, therefore, investigated in vivo and in vitro. Both compounds (0.1 mg/kg−1 i.p.) were able to reverse the amnesia induced by the AMPA receptor antagonist NBQX (30 mg/kg−1 i.p.) in the mouse passive avoidance test. At the effective doses, the investigated compounds did not impair motor coordination, as revealed by the rota rod test, nor modify spontaneous motility and inspection activity, as revealed by the hole board test. DM 232 and DM 235 reversed the antagonism induced by kynurenic acid of the NMDA-mediated release of [3H]NA in the kynurenate test performed in rat hippocampal slices. This effect was abolished by NBQX. DM 232 increases, in a concentration dependent manner, excitatory synaptic transmission in the rat hippocampus in vitro. These results suggest that DM 232 and DM 235 act as cognition enhancers through the activation of the AMPA-mediated neurotransmission system.

Keywords

DM 232 Unifiram DM 235 Sunifiram Kynurenate test Ampakine Learning and memory Passive avoidance 

References

  1. Arai A, Lynch G (1992) Factors regulating the magnitude of long-term potentiation induced by theta pattern stimulation. Brain Res 598:173–184PubMedGoogle Scholar
  2. Arai A, Kessler M, Xiao P, Ambros-Ingerson J, Rogers G, Lynch G (1994) A centrally active drug that modulates AMPA receptor gated currents. Brain Res 638:343–346CrossRefPubMedGoogle Scholar
  3. Arai AC, Kesler M, Rogers G, Lynch G (2000) Effects of the potent ampakine CX614 on hippocampal and recombinant AMPA receptors: interactions with cyclothiazide and GYKI 52466. Mol Pharmacol 58:802–813PubMedGoogle Scholar
  4. Bara H, Hainfellner JA, Kepplinger B, Maral PR, Schmidt H, Budka H (2000) Kynurenic acid metabolism in the brain of HIV-1 infected patients. J Neural Transm 107:1127–1138CrossRefPubMedGoogle Scholar
  5. Baran H, Jellinger K, Deecke L (1999) Kynurenine metabolism in Alzheimer’s disease. J Neural Transm 106:165–181PubMedGoogle Scholar
  6. Bleakman, Lodge D (1998) Neuropharmacology of AMPA and kainate receptors. Neuropharmacology 37:1187–1204CrossRefPubMedGoogle Scholar
  7. Bliss TVP, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39PubMedGoogle Scholar
  8. Burchuladze R, Rose SP (1992) Memory formation in day-old chicks requires NMDA but not non-NMDA glutamate receptors. Eur J Neurosci 4:533–538PubMedGoogle Scholar
  9. Cammarota M, Izquierdo I, Wolfman C, Levi de Stein M, Bernabeu R, Jerusalinsky D, Medina JH (1995) Inhibitory avoidance training induces rapid and selective changes in [3H]AMPA receptor binding in the rat hippocampal formation. Neurobiol Learn Mem 64:257–264CrossRefPubMedGoogle Scholar
  10. Cammarota M, Bernabeu R, Izquierdo I, Medina JH (1996) Reversible changes in hippocampal 3H-AMPA binding following inhibitory avoidance training in the rat. Neurobiol Learn Mem 66:85–88CrossRefPubMedGoogle Scholar
  11. Filliat P, Pernot-Marino I, Baubichon D, Lallement G (1998) Behavioural effect of NBQX, a competitive antagonisty of the AMPA receptors. Pharmacol Biochem Behav 59:1087–1092CrossRefPubMedGoogle Scholar
  12. Ghelardini C, Galeotti N, Gualtieri F, Manetti D, Bucherelli C, Baldi E, Bartolini A (2002a) The novel nootropic compound DM 232 (unifiram) ameliorates memory impairment in mice and rats. Drug Dev Res 56:23–32CrossRefGoogle Scholar
  13. Ghelardini C, Galeotti N, Gualtieri F, Romanelli MN, Bucherelli C, Baldi E, Bartolini A (2002b) DM 235 (sunifiram): a novel nootropic with potential as cognitive enhancer. Naunyn-Schmiedebergs Arch Pharmacol 365:419–426Google Scholar
  14. Gouliaev AH, Senning A (1994) Piracetam and other structurally related nootropics. Brain Res Rev 19:180–222PubMedGoogle Scholar
  15. Gramsbergen JB, Schimdt W, Turski WA, Schwarz R (1992) Age related changes in kynurenic acid production in rat brain. Brain Res 588:1–5PubMedGoogle Scholar
  16. Granger R, Deadwyler S, Davis M, Moskovitz B, Kessler M, Rogers G, Lynch G (1996) Facilitation of glutamate receptors reverses an age-associated memory impairment in rats. Synapse 22:332–337CrossRefPubMedGoogle Scholar
  17. Gualtieri F, Manetti D, Romanelli MN, Ghelardini C (2002) Design and study of piracetam-like nootropics, controversial members of the problematic class of cognition-enhancing drugs. Curr Pharm Design 8:125–138Google Scholar
  18. Hampson RE, Rogers G, Lynch G, Deadwyler SA (1998a) Facilitative effects of the ampakine CX516 on short-term memory in rats: enhancement of delayed-nonmatch-to-sample performance. J Neurosci 18:2740–2747PubMedGoogle Scholar
  19. Hampson RE, Rogers G, Lynch G, Deadwyler SA (1998b) Facilitative effects of the ampakine CX516 on short-term memory in rats: correlations with hippocampal neuronal activity. J Neurosci 18:2748–2763PubMedGoogle Scholar
  20. Hodgkiss JP, Kelly JS (2001) Effect of FK960, a putative cognitive enhancer, on synaptic transmission in CA1 neurons of rat hippocampus. J Pharmacol Exp Ther 297:620–628PubMedGoogle Scholar
  21. Hollmann M, Heinemann S (1994) Cloned glutamate receptors. Annu Rev Neurosci 17:31–108PubMedGoogle Scholar
  22. Jarvik ME, Kopp R (1967) An improved one-trial passive avoidance learning situation. Psychol Rep 21:221–224Google Scholar
  23. Kim M, Campeau S, Falls WA, Davis M (1993) Infusion of the non-NMDA receptor antagonist CNQX into the amygdala blocks the expression of fear-potentiated startle. Behav Neural Biol 59:5–8PubMedGoogle Scholar
  24. Kuribara H, Higuchi Y, Takadoro S (1977) Effects of central depressants on rota-rod and traction performances in mice. Jpn J Pharmacol 27:117–126PubMedGoogle Scholar
  25. Larson J, Lieu T, Petchpradub V, LeDuc B, Ngo H, Rogers GA, Lynch G (1995) Facilitation of olfactory learning by a modulator of AMPA receptors. J Neurosci 15:8023–8030PubMedGoogle Scholar
  26. Lynch G, Kessler M, Rogers G, Ambros-Ingerson J, Granger R, Schehr RS (1996) Psychological effects of a drug that facilitates brain AMPA receptors. Int Clin Psychopharmacol 11:13–19Google Scholar
  27. Malenka RC, Nicoll RA (1993) NMDA-receptor-dependent synaptic plasticity: multiple forms and mechanisms. Trends Neurosci 16:521–527CrossRefPubMedGoogle Scholar
  28. Manetti D, Borea PA, Ghelardini C, Gualtieri F, Romanelli MN, Scapecchi S, Valle G (1997) Reduced-flexibility hybrids of the nicotinic agonists 1,1-dimethyl-4-acetylpiperazinium iodide and 2-(dimethylamino)methyl-5-methyl-cyclopentanone methiodide. Med Chem Res 7:301–312Google Scholar
  29. Manetti D, Ghelardini C, Bartolini A, Bellucci C, Dei S, Galeotti N, Gualtieri F, Romanelli MN, Scapecchi S, Teodori E (2000a) Design, synthesis and preliminary pharmacological evaluation of 1,4-diazabicyclo[4.3.0.]nonan-9-ones as a new class of highly potent nootropic agents. J Med Chem 43:1969–1974CrossRefPubMedGoogle Scholar
  30. Manetti D, Ghelardini C, Bartolini A, Dei S, Galeotti N, Gualtieri F, Romanelli MN, Teodori E (2000b) Molecular simplification of 1,4-diazabicyclo[4.3.0.]nonan-9-ones gives piperazine derivatives that maintain high nootropic activity. J Med Chem 43:4499–4507Google Scholar
  31. Moroni F (1999) Tryptophan metabolism and brain function: focus on kynurenine and other indole metabolites. Eur J Pharmacol 375:87–100Google Scholar
  32. Moroni F, Russi P, Lombardi G, Beni M, Carla V (1988) Presence of kynurenic acid in the mammalian brain. J Neurochem 51:177–180PubMedGoogle Scholar
  33. Novak L, Bregestovski P, Asher P, Herbert A, Prochantz A (1984) Magnesium gates glutamate-activated channels in mouse central neurones. Nature (Lond) 307:462–465Google Scholar
  34. Pittaluga A, Pattarini R, Raiteri M (1995) Putative cognition enhancers reverse kynurenic acid antagonism at hippocampal NMDA receptors. Eur J Pharmacol 272:203–209CrossRefPubMedGoogle Scholar
  35. Pittaluga A, Vaccari D, Raiteri M (1997) The “kynurenate test”, a biochemical assay for putative cognition enhancers. J Pharmacol Exp Ther 283:82–90PubMedGoogle Scholar
  36. Pittaluga A, Bonfanti A, Arvigo D, Raiteri M (1999) Aniracetam, 1-BCP and cyclothiazide differentially modulate the function of NMDA and AMPA receptors mediating enhancement of noradrenaline release in rat hippocampal slices. Naunyn-Schmiedebergs Arch Pharmacol 359:272–279Google Scholar
  37. Pittaluga A, Feligioni M, Ghersi C, Gemignani A, Raiteri M (2001) Potentiation of NMDA receptor function through somatostatin release: a possible mechanism for the cognition-enhancing activity of GABA(B) receptor antagonists. Neuropharmacology 41:301–310CrossRefPubMedGoogle Scholar
  38. Pugliese AM, Passani MB, Pepeu G, Corradetti R (1996) Felbamate decreases synaptic transmission in the CA1 region of rat hippocampal slices. J Pharmacol Exp Ther 279:1100–1108PubMedGoogle Scholar
  39. Quillfeldt JA, Schmitz PK, Walz R, Bianchin M, Zanatta MS, Medina JH, Izquierdo I (1994) CNQX infused into entorhinal cortex blocks memory expression, and AMPA reverses the effect. Pharmacol Biochem Behav 48:437–440CrossRefPubMedGoogle Scholar
  40. Sheardown MJ, Nielsen E O, Hansen AJ, Jacobsen P, Honorè T (1990) 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline: a neuroprotectant for cerebral ischemia. Science 247:571–574PubMedGoogle Scholar
  41. Staubli U, Perez Y, Xu FB, Rogers G, Ingvar M, Stone-Elander S, Lynch G (1994a) Centrally active modulators of glutamate receptors facilitate the induction of long-term potentiation in vivo. Proc Natl Acad Sci USA 91:11158–11162PubMedGoogle Scholar
  42. Staubli U, Rogers G, Lynch G (1994b) Facilitation of glutamate receptors enhances memory. Proc Natl Acad Sci USA 91:777–781PubMedGoogle Scholar
  43. Steele RJ, Stewart MG (1995) Involvement of AMPA receptors in maintenance of memory for a passive avoidance task in day-old domestic chicks (Gallus domesticus) Eur J Neurosci 7:1297–1304Google Scholar
  44. Stone TW (1993) Neuropharmacology of quinolinic and kynurenic acids. Pharmacol Rev 45:309–379PubMedGoogle Scholar
  45. Tocco G, Maren S, Shors TJ, Baudry M, Thompson RF (1992) Long-term potentiation is associated with increased [3H]AMPA binding in rat hippocampus. Brain Res 573:228–234CrossRefPubMedGoogle Scholar
  46. Turski WA, Nakamura M, Todd WP, Carpenter BK, Whetsell WO Jr, Schwarcz R (1988) Identification and quantification of kynurenic acid in human brain tissue. Brain Res 454:164–169PubMedGoogle Scholar
  47. Yamada KA (2000) Therapeutic potential of positive AMPA receptor modulators in the treatment of neurological disease. Exp Opin Invest Drugs 9:765–768Google Scholar
  48. Zivkovic I, Thompson DM, Bertolino M, Uzunov D, DiBella M, Costa E, Guidotti A (1995) 7-Chloro-3-methyl-3–4-dihydro-2H-1,2,4 benzothiadiazine S,S-dioxide (IDRA 21): a benzothiadiazine derivative that enhances cognition by attenuating DL-alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA) receptor desensitization. J Pharmacol Exp Ther 272:300–309PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • N. Galeotti
    • 1
  • C. Ghelardini
    • 1
  • A. Pittaluga
    • 3
  • A. M. Pugliese
    • 1
  • A. Bartolini
    • 1
  • D. Manetti
    • 2
  • M. N. Romanelli
    • 2
  • F. Gualtieri
    • 2
  1. 1.Department of Preclinical and Clinical PharmacologyUniversity of FlorenceFlorenceItaly
  2. 2.Department of Pharmaceutical SciencesUniversity of FlorenceFlorenceItaly
  3. 3.Department of Experimental Medicine, Pharmacology and Toxicology SectionUniversity of GenoaGenoaItaly

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