Cholinomimetic Replacement of Cholinergic Function in Alzheimer Disease

  • Ezio Giacobini
Part of the Advances in Behavioral Biology book series (ABBI, volume 40)


Strong evidence in favor of the role of cholinergic deficits in memory loss and cognitive dysfunction in Alzheimer disease (AD) has suggested cholinergic intervention as a means of reducing symptom intensity and improving function (Giacobini and Becker, 1989; Giacobini, 1990).


Alzheimer Disease Cholinesterase Inhibitor Nucleus Basalis Acetylcholine Release Alzheimer Disease Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Ahlin, A., Nyback, H., Junthe, T., Ohman, G. and Nordgren, L, 1991, THA in Alzheimer’s dementia — clinical, biochemical and pharmacokinetic findings, in:“Alzheimer’s Disease — Basic Mechanisms, Diagnosis and Therapeutic Strategies”, K. Iqbal, D.R.C. McLachlan, B. Winblad and H. Wisniewski, eds., Wiley, New York, pp. 621–625.Google Scholar
  2. Arneric, S.P., 1989, Cortical cerebral blood flow is modulated by cholinergic basal forebrain neurons — effects of ibotenic acid lesions and electrical stimulation, in:“Neurotransmission and Cerebrovascular Function, Vol. 1”, J. Seylaz and E.G. MacKenzie, eds, Excerpta Medica, Amsterdam, pp. 381–384.Google Scholar
  3. Arneric, S.P. and Linville, D.G., 1989, Selective age-related impairment of basal forebrain-elicited increases in cortical cerebral blood flow. Neurobiol Aging 11 (1): 73.Google Scholar
  4. Arneric, S.P., Linville, D.G., Williams, S. and Giacobini, E., 1991, Heptyl-physostigmine (heptastigmine, MF-201) enhances basal forebrain-elicited increases in cortical cerebral blood flow. Second Intl Springfield Alzheimer Symp Abst, pp. 4.Google Scholar
  5. Atack, J.R., Perry, E.K., Bonham, J.R., Perry, R.H., Tomlinson, B.E., Blessed, G. and Fairbairn, A., 1983, Molecular forms of acetylcholinesterase in senile dementia of Alzheimer type-selective loss of the intermediate (lOS) form. Neurosci Lett 40: 199–204.PubMedCrossRefGoogle Scholar
  6. Atack, J.R., Perry, E.K., Bonham, J.R., Candy, J.M. and Perry, R.H., 1987, Molecular forms of butyrylcholinesterase in the human neocortex during development and degeneration of the cortical cholinergic system. J Neurochem 48 (6): 1687–1692.PubMedCrossRefGoogle Scholar
  7. Atack, J.R., Yu, Q-S., Soncrant, T.T., Brossi, A. and Rapoport, S.I., 1989, Comparative inhibitory effects of various physostigmine analogs against acetyl- and butyrylcholinesterases. J Pharm Exp Therapy 249: 194–202.Google Scholar
  8. Bartels, E. and Nachmansohn, D., 1969, Organophosphate inhibitors of acetylcholine-receptor and acetylcholinesterase tested on the electroplax. Arch Biochem Biophys 133: 1–23.PubMedCrossRefGoogle Scholar
  9. Becker, R.E. and Giacobini, E., 1988a, Mechanisms of Cholinesterase inhibition in Senile Dementia of the Alzheimer Type-clinical, pharmacological and therapeutic aspects. Drug Dev Res 12: 163–195.CrossRefGoogle Scholar
  10. Becker, R.E. and Giacobini, E., 1988b, Pharmacokinetics and pharmacodynamics of acetylcholinesterase inhibition — can acetylcholine levels in brain be improved in Alzheimer’s disease? Drug Dev Res 14: 235–246.CrossRefGoogle Scholar
  11. Becker, R.E., Colliver, J., Elble, R., Feldman, E., Giacobini, E., Kumar, V., Markwell, S., Moriearty, P., Parks, R., Shillcutt, S., Unni, L., Vicari, S., Womack, C. and Zec, R., 1990, Effects of metrifonate, a long-acting Cholinesterase inhibitor in Alzheimer’s disease — report of an open trial. Drug Dev Res 19: 425–434.CrossRefGoogle Scholar
  12. Biesold, D., Inanami, O., Sato, A. and Sato, Y., 1989, Stimulation of the nucleus basalis of Meynert increases cerebral cortical blood flow in rats. Neurosci Lett 98: 39–44.PubMedCrossRefGoogle Scholar
  13. Bigl, V., Woolf, NJ and Butcher, L.L., 1982, Cholinergic projections from the basal forebrain to frontal, parietal, temporal, occipital and cingulate cortices — a combined fluorescent tracer and acetylcholinesterase analysis. Brain Res Bull 8: 727–749.PubMedCrossRefGoogle Scholar
  14. Bisso, G.M., Diana, G., Fortuna, S., Meneguz, A. and Michalek, H., 1988, Change in the distribution of acetylcholinesterase molecular forms in frontoparietal cortex of the rat following nucleus basalis lesions with kainic acid. Brain Res 449: 391–394.PubMedCrossRefGoogle Scholar
  15. Buyukuysal, R.L., Holmes, T.C. and Wurtman, R.J., 1991, Interactions of 3, 4-diaminopyridine and choline in stimulating acetylcholine release and protecting membrane phospholipids. Brain Res 541: 1–6.PubMedCrossRefGoogle Scholar
  16. Damsma, G., Westerink, B.H.C., de Vries, J.B., Van den Berg, C.J. and Horn, A.S., 1987, Measurement of acetylcholine release in freely moving rats by means of automated intracerebral dialysis. J Neurochem 48: 1523–1528.Google Scholar
  17. DeSarno, P., Pomponi, M., Giacobini, E., Tang, X.C. and Williams, E., 1989, The effect of heptyl-physostigmine, a new Cholinesterase inhibitor, on the central cholinergic system of the rat. Neurochem Res 14 (10): 971–977.CrossRefGoogle Scholar
  18. Elble, R., Giacobini, E., Becker, R., Zee, R., Vicari, S., Womack, C., Williams, E. and Higgins, C., 1988, Treatment of Alzheimer dementia with steady-state infusion of physostigmine, in, “Current Research in Alzheimer Therapy,” E. Giacobini and R. Becker, eds, Taylor and Francis, New York, pp. 123–140.Google Scholar
  19. Eldefrawi, M.E., Dedefrawi, A.T. and O’Brien, R.D., 1971, Binding of five cholinergic ligands to housefly brain and Torpedo electroplax:relationship to acetylcholine receptors. Mol Pharmacol 7: 104–111.PubMedGoogle Scholar
  20. Fibiger, H.C., 1982, The organization and some projections of cholinergic neurons of the mammalian forebrain. Brain Res Rev 4: 327–388.CrossRefGoogle Scholar
  21. Fishman, E.B., Siek, G.C., MacCallum, R.D., Bird, E.D., Volicer, L. and Marquis, J.K., 1986, Distribution of the molecular forms of acetylcholinesterase in human brain — alterations in dementia of the Alzheimer type. Ann Neurol 19: 246–252.PubMedCrossRefGoogle Scholar
  22. Giacobini, E., 1990, The cholinergic system in Alzheimer disease, in:“Progress in Brain Research, Vol. 84”, S-M. Aquilonius and P-G. Gillberg, eds., Elsevier, Amsterdam, pp. 321–332.Google Scholar
  23. Giacobini, E. and Becker, R., 1989, Advances in the therapy of Alzheimer’s disease, in:“Familial Alzheimer’s Disease — Molecular Genetics and Clinical Perspectives”, G.D. Miner, R. Richter, J.P. Blass, J.L. Valentine and L.A. Winters-Miner, eds., Marcel Dekker Inc., New York, pp. 223–268.Google Scholar
  24. Giacobini, E. and Becker, R., 1991, New Cholinesterase inhibitors for treatment of Alzheimer’s disease, in:“Alzheimer’s Disease:Basic Mechanisms, Diagnosis and Therapeutic Strategies”, K. Iqbal, D.R.C. McLachlan, B. Winblad and H.M. Wisniewski, eds., John Wiley & Sons Ltd., New York, pp. 627–631.Google Scholar
  25. Giacobini, E., Becker, R., Mcllhany, M. and Kumar, V., 1988a, Intracerebroventricular administration of cholinergic drugs:preclinical trials and clinical experience in Alzheimer patients, in:“Current Research in Alzheimer Therapy:Cholinesterase Inhibitors”, E. Giacobini and R. Becker, eds, Taylor and Francis, New York, pp. 113–122.Google Scholar
  26. Giacobini, E., DeSarno, P., Mcllhany, M. and Clark, B., 1988b, The cholinergic receptor system in the frontal lobe of Alzheimer patients, in:“Nicotinic Acetylcholine Receptors in the Nervous System, NATO ASI Series, Vol. H25”, F. Clementi, C. Gotti and E. Sher, eds., Springer-Verlag, Berlin, pp. 367–378.Google Scholar
  27. Hallak, M. and Giacobini, E., 1987, A comparison of the effects of two inhibitors on brain Cholinesterase. Neuropharmacology 26 (6): 521–530.PubMedCrossRefGoogle Scholar
  28. Hallak, M. and Giacobini, E., 1989, Physostigmine, tacrine and metrifonate — the effect of multiple doses on acetylcholine metabolism in rat brain. Neuropharmacology 28 (3): 199–206.PubMedCrossRefGoogle Scholar
  29. Hanin, I., Tang X-C and Kozikowski, A.P., 1991, Clinical and preclinical studies with Huperzine, in:“Cholinergic Basis of Alzheimer Therapy”, R. Becker and E. Giacobini, eds, Birkhauser, Boston, ( In Press).Google Scholar
  30. Kurosawa, M., Sato, A. and Sato, Y., 1989a, Stimulation of the nucleus basalis of Meynert increases acetylcholine release in the cerebral cortex in rats. Neurosci Lett 98: 45–50.PubMedCrossRefGoogle Scholar
  31. Kurosawa, M., Sato, A. and Sato, Y., 1989b, Well-maintained responses of acetylcholine release and blood flow in the cerebral cortex to focal electrical stimulation of the nucleus basalis of Meynert in aged rats. Neurosci Lett 100: 198–202.PubMedCrossRefGoogle Scholar
  32. Lacombe, P., Sercombe, R., Dauphin, F., Philipson, V. and Seylaz, J., 1989a, Cortical blood flow response to stimulation of cholinergic neurons of the substantia innominata in young and senescent rats, in:“Neurotransmission and Cerebrovascular Function, Vol. 1”, J. Seylaz and E.T. MacKenzie, eds, Elsevier, Amsterdam, pp. 385–388.Google Scholar
  33. Lacombe, P., Sercombe, R., Verrecchia, C., Philipson, V., MacKenzie, E.T. and Seylaz, J., 1989b, Cortical blood flow increases induced by stimulation of the substantia innominata in the unanesthetized rat. Brain Res 491: 1–14.PubMedCrossRefGoogle Scholar
  34. Messamore, E., Ogane, N., Giacobini, E. and Williams, E., 1990, Effect of the physostigmine derivative heptastigmine on acetylcholine release assessed by microdialysis in rat brain. Soc Neurosci Abst 16: 1307 (540.8).Google Scholar
  35. Messamore, E., Warpman, U., Ogane, N. and Giacobini, E., 1991, Effect of heptyl-physostigmine on cholinergic dynamics in rat cerebral cortex. Second Intl Springfield Alzheimer Sym Abst pp. 36.Google Scholar
  36. Ogane, N., Takada, Y., Iga, Y., Kawanishi, G. and Mizobe, F., 1990, Effects of Ml muscarinic receptor agonist on the central cholinergic system, evaluated by brain microdialysis. Neurosci Lett 114: 95–100.PubMedCrossRefGoogle Scholar
  37. Ogane, N., Messamore, E. and Giacobini, E., 1991, Do cholinesterase inhibitors preferentially inhibit certain molecular form s of brain cholinesterase? Second Intl Springfield Alzheimer Symp Abst pp. 43.Google Scholar
  38. Pomponi, M., Giacobini, E. and Brufani, M., 1990, Present state and future development of the therapy of Alzheimer disease. Aging 2: 125–153.PubMedGoogle Scholar
  39. Rogers, S.L., Yamanishi, Y., Yamatsu, K. and Mihara, M., 1991, E2020:preclinical and clinical experience. Second Intl Springfield Alzheimer Symp Abst, pp. 40.Google Scholar
  40. Schroder, H., 1991, Immunocytochemistry of muscarinic and nicotinic receptors in human brain, in:“Cholinergic Basis of Alzheimer Therapy”, R. Becker and E. Giacobini, eds, Birkhauser, Boston (In Press).Google Scholar
  41. Scremin, O.U., Rovere, A.A., Raynald, A.C. and Giardini, A., 1973, Cholinergic control of blood flow in the cerebral cortex of the rat. Stroke 4: 232–239.CrossRefGoogle Scholar
  42. Scremin, O.U., Scremin, A.M.E., Somani, S.M. and Giacobini, E., 1990, Brain regional distribution of physostigmine and its relation to cerebral blood flow following intravenous administration in rats. J Neurosci Res 26: 188–195.PubMedCrossRefGoogle Scholar
  43. Scremin, O.U., Torres, C., Scremin, A.M.E., O’Neal, M., Heuser, D. and Blisard, K.S., 1991, Role of nucleus basalis in cholinergic control of cortical blood flow. J Neurosci Res 28: 382–390.PubMedCrossRefGoogle Scholar
  44. Sherman, K.A., Kumar, V., Ashford, J.W., Murphy, J.W., Elble, R.J. and Giacobini, E., 1987, Effect of oral physostigmine in senile dementia patients — utility of blood cholinesterase inhibition and neuroendocrine responses to define pharmacokinetics and pharmacodynamics, in:“Central Nervous System Disorders of Aging — Clinical Intervention and Research (Aging, Vol. 33)”, R. Strong, W. G. Wood and W.J. Burke, eds, Raven Press, New York, pp. 77–90.Google Scholar
  45. Tang, X.C., DeSarno, P., Sugaya, K. and Giacobini, E., 1989, Effect of huperzine A, a new cholinesterase inhibitor, on the central cholinergic system of the rat. J Neurosci Res 24: 276–285.PubMedCrossRefGoogle Scholar
  46. Thomsen, T., Zendeh, B., Fischer, J.P. and Kewitz, H., 1991, In vitro effects of various cholinesterase inhibitors on acetyl — and butyrylcholinesterase of healthy volunteers. Biochem Pharmacol 41 (1): 139–141.PubMedCrossRefGoogle Scholar
  47. Unni, L.K., Becker, R.E., Hutt, V. and Imbimbo, B.P., 1990, Inhibition of acetylcholinesterase and butyrylcholinesterase after oral administration of heptastigmine in healthy volunteers. IUPHAR Congress (Amsterdam), p. 246.Google Scholar
  48. Unni, L.K, Womack, C., Moriearty, P.L., Hannant, M.E. and Becker, R.E., 1991, Clinical pharmacokinetics and pharmacodynamics of metrifonate. Second Intl Springfield Alzheimer Symp Abst, pp. 59.Google Scholar
  49. Younkin, S.G., Goodridge, B., Katz, J., Locken, G., Nafziger, D., Usiak, M.F. and Younkin, L.H., 1986, Molecular forms of acetylcholinesterases in Alzheimer’s disease. Fed Proc 45 (13): 2982–2988.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1992

Authors and Affiliations

  • Ezio Giacobini
    • 1
  1. 1.Department of Pharmacology, Southern IllinoisUniversity School of MedicineSpringfieldUSA

Personalised recommendations