Skip to main content

Advertisement

Log in

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

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6A, B

Similar content being viewed by others

References

  • Arai A, Lynch G (1992) Factors regulating the magnitude of long-term potentiation induced by theta pattern stimulation. Brain Res 598:173–184

    CAS  PubMed  Google Scholar 

  • 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 638:343–346

    Article  CAS  PubMed  Google Scholar 

  • 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 58:802–813

    CAS  PubMed  Google Scholar 

  • 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 107:1127–1138

    Article  CAS  PubMed  Google Scholar 

  • Baran H, Jellinger K, Deecke L (1999) Kynurenine metabolism in Alzheimer’s disease. J Neural Transm 106:165–181

    CAS  PubMed  Google Scholar 

  • Bleakman, Lodge D (1998) Neuropharmacology of AMPA and kainate receptors. Neuropharmacology 37:1187–1204

    Article  CAS  PubMed  Google Scholar 

  • Bliss TVP, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39

    CAS  PubMed  Google Scholar 

  • Burchuladze R, Rose SP (1992) Memory formation in day-old chicks requires NMDA but not non-NMDA glutamate receptors. Eur J Neurosci 4:533–538

    PubMed  Google Scholar 

  • 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 64:257–264

    Article  CAS  PubMed  Google Scholar 

  • 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 66:85–88

    Article  CAS  PubMed  Google Scholar 

  • Filliat P, Pernot-Marino I, Baubichon D, Lallement G (1998) Behavioural effect of NBQX, a competitive antagonisty of the AMPA receptors. Pharmacol Biochem Behav 59:1087–1092

    Article  CAS  PubMed  Google Scholar 

  • 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 56:23–32

    Article  CAS  Google Scholar 

  • 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 365:419–426

  • Gouliaev AH, Senning A (1994) Piracetam and other structurally related nootropics. Brain Res Rev 19:180–222

    CAS  PubMed  Google Scholar 

  • Gramsbergen JB, Schimdt W, Turski WA, Schwarz R (1992) Age related changes in kynurenic acid production in rat brain. Brain Res 588:1–5

    CAS  PubMed  Google Scholar 

  • 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 22:332–337

    Article  CAS  PubMed  Google Scholar 

  • 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 8:125–138

    CAS  Google Scholar 

  • 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 18:2740–2747

    CAS  PubMed  Google Scholar 

  • 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 18:2748–2763

    CAS  PubMed  Google Scholar 

  • 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 297:620–628

    CAS  PubMed  Google Scholar 

  • Hollmann M, Heinemann S (1994) Cloned glutamate receptors. Annu Rev Neurosci 17:31–108

    CAS  PubMed  Google Scholar 

  • Jarvik ME, Kopp R (1967) An improved one-trial passive avoidance learning situation. Psychol Rep 21:221–224

    CAS  Google Scholar 

  • 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 59:5–8

    CAS  PubMed  Google Scholar 

  • Kuribara H, Higuchi Y, Takadoro S (1977) Effects of central depressants on rota-rod and traction performances in mice. Jpn J Pharmacol 27:117–126

    CAS  PubMed  Google Scholar 

  • 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 15:8023–8030

    CAS  PubMed  Google Scholar 

  • 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 11:13–19

    CAS  Google Scholar 

  • Malenka RC, Nicoll RA (1993) NMDA-receptor-dependent synaptic plasticity: multiple forms and mechanisms. Trends Neurosci 16:521–527

    Article  CAS  PubMed  Google Scholar 

  • 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 7:301–312

    CAS  Google Scholar 

  • 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 43:1969–1974

    Article  CAS  PubMed  Google Scholar 

  • 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 43:4499–4507

    CAS  Google Scholar 

  • Moroni F (1999) Tryptophan metabolism and brain function: focus on kynurenine and other indole metabolites. Eur J Pharmacol 375:87–100

    CAS  Google Scholar 

  • Moroni F, Russi P, Lombardi G, Beni M, Carla V (1988) Presence of kynurenic acid in the mammalian brain. J Neurochem 51:177–180

    CAS  PubMed  Google Scholar 

  • Novak L, Bregestovski P, Asher P, Herbert A, Prochantz A (1984) Magnesium gates glutamate-activated channels in mouse central neurones. Nature (Lond) 307:462–465

    Google Scholar 

  • Pittaluga A, Pattarini R, Raiteri M (1995) Putative cognition enhancers reverse kynurenic acid antagonism at hippocampal NMDA receptors. Eur J Pharmacol 272:203–209

    Article  CAS  PubMed  Google Scholar 

  • Pittaluga A, Vaccari D, Raiteri M (1997) The “kynurenate test”, a biochemical assay for putative cognition enhancers. J Pharmacol Exp Ther 283:82–90

    CAS  PubMed  Google Scholar 

  • 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 359:272–279

    Google Scholar 

  • 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 41:301–310

    Article  CAS  PubMed  Google Scholar 

  • 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 279:1100–1108

    CAS  PubMed  Google Scholar 

  • 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 48:437–440

    Article  CAS  PubMed  Google Scholar 

  • 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 247:571–574

    CAS  PubMed  Google Scholar 

  • 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 91:11158–11162

    CAS  PubMed  Google Scholar 

  • Staubli U, Rogers G, Lynch G (1994b) Facilitation of glutamate receptors enhances memory. Proc Natl Acad Sci USA 91:777–781

    CAS  PubMed  Google Scholar 

  • 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 7:1297–1304

    Google Scholar 

  • Stone TW (1993) Neuropharmacology of quinolinic and kynurenic acids. Pharmacol Rev 45:309–379

    CAS  PubMed  Google Scholar 

  • 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 573:228–234

    Article  CAS  PubMed  Google Scholar 

  • 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 454:164–169

    CAS  PubMed  Google Scholar 

  • Yamada KA (2000) Therapeutic potential of positive AMPA receptor modulators in the treatment of neurological disease. Exp Opin Invest Drugs 9:765–768

    CAS  Google Scholar 

  • 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 272:300–309

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to C. Ghelardini.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Galeotti, N., Ghelardini, C., Pittaluga, A. et al. AMPA-receptor activation is involved in the antiamnesic effect of DM 232 (unifiram) and DM 235 (sunifiram). Naunyn-Schmiedeberg's Arch Pharmacol 368, 538–545 (2003). https://doi.org/10.1007/s00210-003-0812-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-003-0812-6

Keywords

Navigation