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Psychopharmacology

, 207:201 | Cite as

Effects of dimethylaminoethanol pyroglutamate (DMAE p-Glu) against memory deficits induced by scopolamine: evidence from preclinical and clinical studies

  • Olivier Blin
  • Christine Audebert
  • Séverine Pitel
  • Arthur Kaladjian
  • Catherine Casse-Perrot
  • Mohammed Zaim
  • Joelle Micallef
  • Jacky Tisne-Versailles
  • Pierre Sokoloff
  • Philippe Chopin
  • Marc Marien
Original Investigation

Abstract

Rationale

Dimethylaminoethanol pyroglutamate (DMAE p-Glu) is a compound resulting from the reaction between dimethylaminoethanol (an indirect precursor of acetylcholine) and pyroglutamic acid (a cyclic derivative of glutamic acid having procholinergic properties and promnesic effects in both animals and man).

Objectives

The present study undertook preclinical and clinical evaluations to test a potential therapeutic utility for DMAE p-Glu in cognitive impairments related to central cholinergic deficit.

Materials and methods

In preclinical study, DMAE p-Glu was studied in rats by intracerebral microdialysis in conscious freely moving animals, on performance of rats in the Morris water maze test of spatial memory, and on the deficit in passive avoidance behavior induced by scopolamine. The clinical study examined the effect of DMAE p-Glu on cognitive deficits induced by an intravenous injection of scopolamine in healthy young male subjects.

Results

In rat experiments, DMAE p-Glu increased the extracellular levels of choline and acetylcholine in the medial prefrontal cortex, as assessed by intracerebral microdialysis, improved performance in a test of spatial memory, and reduced scopolamine-induced memory deficit in passive avoidance behavior. Clinical study results show that scopolamine induced a memory deficit and that DMAE p-Glu produced a significant positive effect on scores in the Buschke test, as well as a slight but significant difference on choice reaction time.

Conclusion

These results indicate that DMAE p-Glu reduces the deleterious effect of scopolamine on long-term memory in healthy volunteers and suggest that DMAE p-Glu might be effective in reducing memory deficits in patients with cognitive impairment.

Keywords

Dimethylaminoethanol pyroglutamate Scopolamine Cognitive tests Human volunteers Rat Microdialysis 

Notes

Acknowledgments

The authors gratefully acknowledge the excellent technical assistance of Martine Mas (CRPF) in performing the rat microdialysis experiments and HPLC analyses and Pascale Petiot (CRPF) in performing the rat behavioral experiments. Experiments comply with the current laws of the country as they were performed.

References

  1. Antonelli T, Carlà V, Lambertini L, Moroni F, Bianchi C (1984) Pyroglutamic acid administration modifies the electrocorticogram and increases the release of acetylcholine and GABA from the guinea-pig cerebral cortex. Pharmacol Res Commun 16:189–197CrossRefPubMedGoogle Scholar
  2. Bond A, Lader M (1974) The use of analogue scales in rating subjective feelings. Br J Med Psychol 47:211–218Google Scholar
  3. Bozzali M, MacPherson SE, Dolan RJ, Shallice T (2006) Left prefrontal control of novel occurrence during recollection: a psychopharmacological study using scopolamine and event-related fMRI. NeuroImage 33:286–295CrossRefPubMedGoogle Scholar
  4. Breese CR, Lee MJ, Adams CE, Sullivan B, Logel J, Gillen KM, Marks MJ, Collins AC, Leonard S (2000) Abnormal regulations of high affinity nicotinic receptors in subjects with schizophrenia. Neuropsychopharmacology 23:351–364CrossRefPubMedGoogle Scholar
  5. Buschke H (1973) Selective reminding for analysis of memory and learning. J Verbal Learn Verbal BehavGoogle Scholar
  6. Caine ED, Weingartner H, Ludlow DL, Cudahy EA, Wehry S (1981) Qualitative analysis of scopolamine-induced amnesia. Psychopharmacology 74:74–80CrossRefPubMedGoogle Scholar
  7. Chopin P, Briley M (1992) Effects of four non-cholinergic cognitive enhancers in comparison with tacrine and galanthamine on scopolamine-induced amnesia in rats. Psychopharmacology 106:26–30CrossRefPubMedGoogle Scholar
  8. Chopin P, Colpaert FC, Marien M (2002) Effects of acute and subchronic administration of dexefaroxan, an alpha(2)-adrenoceptor antagonist, on memory performance in young adult and aged rodents. J Pharmacol Exp Ther 301:187–196CrossRefPubMedGoogle Scholar
  9. Coyle JT, Price DL, DeLong MR (1983) Alzheimer's disease: a disorder of cortical cholinergic innervation. Science 219:1184–1190CrossRefPubMedGoogle Scholar
  10. Damsma G, Lammerts van Bueren D, Westerink BHC, Horn AS (1987) Determination of acetylcholine and choline in the femtomole range by means of HPLC, a postcolumn enzyme reactor, and electrochemical detection. Chromatographia 24:827–831CrossRefGoogle Scholar
  11. Drachman DA (1977) Memory and cognitive function in man: does the cholinergic system have a specific role? Neurology 27:783–790PubMedGoogle Scholar
  12. Drachman DA, Leavitt J (1974) Human memory and the cholinergic system: a relationship to aging? Arch Neurol 30:113–121PubMedGoogle Scholar
  13. Drago F, Continella G, Valerio C, D’Agata V, Astuto C, Spadaro F, Scapagnini U (1987) Effects of pyroglutamic acid on learning and memory processes of the rat. Acta Therapeutica 13:587–594Google Scholar
  14. Ebert U, Oertel R, Kirch W (2000) Influence of grapefruit juice on scopolamine pharmacokinetics and pharmacodynamics in healthy male and female subjects. Int J Clin Pharmacol Ther 38:532–531Google Scholar
  15. Ebert U, Grossmann M, Oertel R, Grammaté T, Kirch W (2001) Pharmacokinetic–pharmacodynamic modeling of the electroencephalogram effects of scopolamine in healthy volunteers. J Clin Pharmacol 41:51–60CrossRefPubMedGoogle Scholar
  16. Edginton T, Rusted J (2003) Separate and combined effects of scopolamine and nicotine on retrieval-induced forgetting. Psychopharmacology 170:351–357CrossRefPubMedGoogle Scholar
  17. Ellis JR, Ellis KA, Bartholomeusz CF, Harrison BJ, Wesnes KA, Erskine FF, Vitetta L, Nathan PJ (2006) Muscarinic and nicotinic receptors synergistically modulate working memory and attention in humans. The International Journal of Neuropsychopharmacology 9:175–189CrossRefPubMedGoogle Scholar
  18. Erskine FF, Ellis JR, Ellis KA, Stuber E, Hogan K, Miller V, Moore E, Bartholomeusz C, Harrison BJ, Lee B, Phan KL, Liley D, Nathan PJ (2004) Evidence for synergistic modulation of early information processing by nicotinic and muscarinic receptors in humans. Hum Psychopharmacol 19:503–509CrossRefPubMedGoogle Scholar
  19. Flood JF, Smith GE, Cherkin A (1983) Memory retention: potentiation of cholinergic drug combinations in mice. Neurobiol Aging 4:37–43CrossRefPubMedGoogle Scholar
  20. Friedman P (1991) GB-STAT: Computer-aided statistics & graphics, ver 3.0. Silver Spring: Dynamic Microsystems, IncGoogle Scholar
  21. Gage FH, Kelly PAT, Björklund A (1984) Regional changes in brain glucose metabolism reflect cognitive impairments in aged rats. J Neurosci 4:2856–2865PubMedGoogle Scholar
  22. Gilles C, Luthringer R (2007) Pharmacological models in healthy volunteers: their use in the clinical development of psychotropic drugs. Journal of Psycopharmacology 21:272–282CrossRefGoogle Scholar
  23. Glick SD, Zimmerberg B (1972) Amnesic effects of scopolamine. Behav Biol 7:245–254CrossRefPubMedGoogle Scholar
  24. Hall ST, Puech A, Schaffler K, Wesnes K, Gamzu ER (1990) Early clinical testing of cognition enhancers: prediction of efficacy. Pharmacopsychiatry 23:57–58CrossRefPubMedGoogle Scholar
  25. Huang F, Buchwald P, Browne CE, Farag HH, Wu WM, Ji F, Hochhaus G, Bodor N (2001) Receptor binding studies of soft anticholinergic agents. AAPS pharmSci 3:E30CrossRefPubMedGoogle Scholar
  26. Jope RS, Jenden DJ (1979) Dimethylaminoethanol (deanol) metabolism in rat brain and its effect on acetylcholine synthesis. J Pharmacol Exp Ther 211:472–429PubMedGoogle Scholar
  27. Kolb B, Tees RC (1990) The cerebral cortex of the rat. MIT Press, CambridgeGoogle Scholar
  28. McCann UD, Eligulashvili V, Mertl M, Murphy DL, Ricaurte GA (1999) Altered neuroendocrine and behavioral responses to m-chlorophenylpiperazine in 3, 4-methylenedioxymethamphetamine (MDMA) users. Psychopharmacology 147:56–65CrossRefPubMedGoogle Scholar
  29. Martinez R, Molchan SE, Lawlor BA, Thompson K, Martinson H, Latham G, Weingartner H, Sunderland T (1997) Minimal effects of dextroamphetamine on scopolamine-induced cognitive impairments in humans. Biol Psychiatry 41:50–57CrossRefPubMedGoogle Scholar
  30. Mauri M, Sinforiani E, Reverberi F, Merlo P, Bono G (1994) Pramiracetam effects on scopolamine-induced amnesia in healthy volunteers. Arch Gerontol Geriatr 2:133–139CrossRefGoogle Scholar
  31. Mintzer MZ, Griffiths RR (2003) Lorazepam and scopolamine: a single-dose comparison of effects on human memory and attentional processes. Exp clin psychopharmacol 11:56–72CrossRefPubMedGoogle Scholar
  32. Molchan SE, Mellow AM, Lawlor BA, Weingartner HJ, Cohen RM, Cohen MR, Sunderland T (1990) TRH attenuates scopolamine-induced memory impairment in humans. Psychopharmacology 100:84–89CrossRefPubMedGoogle Scholar
  33. Morris RGM (1981) Spatial localization does not require the presence of local cues. Learn Motiv 12:239–260CrossRefGoogle Scholar
  34. Patat A, Klein MJ, Surjus A, Hucher M, Granier J (1991) RU 41 656 does not reverse the scopolamine-induced cognitive deficit in healthy volunteers. Eur J Clin Pharmacol 41:225–231CrossRefPubMedGoogle Scholar
  35. Pepeu G, Freedman GX, Giarman NJ (1960) Biochemical and pharmacological studies of dimethylaminoethanol (deanol). J Pharmacol Exp Ther 129:291–295PubMedGoogle Scholar
  36. Perry EK, Tomlinson BE, Blessed G, Bergmann K, Gibson PH, Perry RH (1978) Correlation of cholinergic abnormalities with senile plaques and mental tests scores in senile dementia. Br Med J 2:1457–1459CrossRefPubMedGoogle Scholar
  37. Potter DD, Pickles CD, Roberts RC, Rugg MD (2000) The effect of cholinergic receptor blockade by scopolamine on memory performance and the auditory P3. Psychophysiology 14:11–23CrossRefGoogle Scholar
  38. Riedel W, Hogervorst E, Leboux R, Verhey F, Van Praag H, Jolles J (1995) Caffeine attenuates scopolamine-induced memory impairment in humans. Psychopharmacology 122:158–168CrossRefPubMedGoogle Scholar
  39. Rusted JM, Warburton DM (1988) The effects of scopolamine on working memory in healthy young volunteers. Psychopharmacology 96:145–152PubMedGoogle Scholar
  40. Sarter M, Bruno JP (1997) Cognitive functions of cortical acetylcholine: toward a unifying hypothesis. Brain Res Brain Res Rev 23:28–46CrossRefPubMedGoogle Scholar
  41. Sarter M, Bruno JP (2000) Cortical cholinergic inputs mediating arousal, attentional processing and dreaming: differential afferent regulation of the basal forebrain by telencephalic and brainstem afferents. Neuroscience 95:933–952CrossRefPubMedGoogle Scholar
  42. Tellez S, Colpaert F, Marien M (1999) α2-Adrenoceptor modulation of cortical acetylcholine release in vivo. Neuroscience 89:1041–1050CrossRefPubMedGoogle Scholar
  43. Terry AV Jr, Buccafusco JJ (2003) The cholinergic hypothesis of age and Alzheimer's disease-related cognitive deficits: recent challenges and their implications for novel drug development. J Pharmacol Exp Ther 306:821–827CrossRefPubMedGoogle Scholar
  44. Vernikos-Danellis J, Winget CM, Leach CS, Rosenblatt LS, Lyman J, Beljan JR (1977) Space motion sickness medications: interference with biomedical parameters. Acta Astronautica 4:1159–1169CrossRefPubMedGoogle Scholar
  45. Wesnes KA (2001) The use of cognitive tests to facilitate drug and dose selection in phase I and to optimize dosing in phase IV. Int Congr Ser 1220:35–50CrossRefGoogle Scholar
  46. Wesnes KA, Simpson PM, Kidd AG (1988) An investigation of the range of cognitive impairments induced by scopolamine 0.6 mg sc. Hum Psychopharmacol 3:27–41CrossRefGoogle Scholar
  47. Wesnes KA, Simpson PM, White L, Pinker S, Jertz G, Murphy M, Siegfried K (1991) Cholinesterase inhibition in the scopolamine model of dementia. Ann N Y Acad Sci 640:268–271PubMedGoogle Scholar
  48. Winkler J, Suhr ST, Gage FH, Thal LJ, Fischer LJ (1995) Essential role of neocortical acetylcholine in spatial memory. Nature 375:484–487CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Olivier Blin
    • 1
  • Christine Audebert
    • 1
  • Séverine Pitel
    • 2
  • Arthur Kaladjian
    • 1
  • Catherine Casse-Perrot
    • 1
  • Mohammed Zaim
    • 3
  • Joelle Micallef
    • 1
  • Jacky Tisne-Versailles
    • 4
  • Pierre Sokoloff
    • 5
  • Philippe Chopin
    • 5
  • Marc Marien
    • 5
  1. 1.CIC-UPCET, UMR CNRS-Université de la Méditerranée 6193, Hôpital de la TimoneMarseille cedex 5France
  2. 2.QualissimaMarseilleFrance
  3. 3.Institut de Recherche Pierre FabreRamonville Saint AgneFrance
  4. 4.Centre Expérimental et Pharmacocinétique de CampansCastresFrance
  5. 5.Centre de Recherche Pierre Fabre (CRPF), 17 Avenue Jean MoulinCastresFrance

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