PDF herunterladen
Pharmacopsychiatry 1999; 32(6): 242-247
DOI: 10.1055/s-1999-7961
Original Paper
Georg Thieme Verlag Stuttgart ·New York

Synergistic Effects of Tetrahydroaminoacridine and Lithium on Cholinergic Function After Excitotoxic Basal Forebrain Lesions in Rat

T. Arendt1 , K. Lehmann2 , G. Seeger1 , U. Gärtner1
  • 1Department of Neuroanatomy, Paul Flechsig Institute of Brain Research, University of Leipzig, Germany
  • 2and Wörwag Pharma GmbH & Co., Böblingen, Germany
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
31. Dezember 1999 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Effects of lithium and tetrahydroaminoacridine (THA), either alone or in combination, were tested in an animal model of excitotoxic cholinergic deafferentation of the cerebral cortex. Rats received ibotenic acid lesions of cholinergic basal forebrain nuclei resulting in a 30 % to 40 % depletion of both cortical choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activity. Lithium as well as THA, given separately either prior or subsequently to the development of the lesion, had small but significant effects on the recovery of cortical ChAT and AChE activity. Applied in combination, these drugs clearly showed synergistic effects. These potentiating actions might be due to neuroprotective/neurotrophic mechanisms as well as to effects on acetylcholine turnover and muscarinic receptor-coupled phosphoinositide turnover. Similar approaches of combination therapy might prove useful for the management of mental disorders associated with cholinergic dysfunction.

References

  • 1 Arendt Th. Pathologische Anatomie der Alzheimerschen Erkrankung. Springer-Verlag, in press 1998
    Google Scholar
  • 2 Arendt Th, Allen Y, Marchbanks R M, Schugens M M, Sinden J, Lantos P L, Gray J A. Cholinergic system and memory in the rat: effects of chronic ethanol, embryonic basal forebrain brain transplants, and excitotoxic lesions of cholinergic basal forebrain projection system.  Neurosci. 1989;  33 435-462
    CrossrefPubMedGoogle Scholar
  • 3 Arendt Th, Allen Y, Sinden J, Schugens M M, Marchbanks R M, Lantos P L, Gray J A. Cholinergic-rich brain transplants reverse alcohol-induced memory deficits.  Nature. 1988;  332 448-450
    CrossrefPubMedGoogle Scholar
  • 4 Arendt Th, Bigl V. The pathology of the human nucleus basalis of Meynert and its implications for a specific therapy. Aus: Becker, R. and E. Giacobini: Cholinergic Basis for Alzheimer Therapy. Birk-häuser-Verlag 1991: 38-45
    Google Scholar
  • 5 Arendt Th, Bigl V, Arendt A, Tennstedt A. Loss of neurons in the Nucleus basalis of Meynert in Alzheimer's disease, Paralysis agitans and Korsakoffs disease.  Acta Neuropathol. 1983;  61 -108
    PubMedGoogle Scholar
  • 6 Arendt Th, Brückner M K, Bigl V, Marcova L. Dendritic reorganization in the basal forebrain under degenerative conditions and its defects in Alzheimer's disease. II. Ageing, Korsakoffs disease, Parkinson's disease, and Alzheimer's disease.  J Comp Neurol. 1995;  351 189-222
    PubMedGoogle Scholar
  • 7 Chen R W, Chuang D M. Long term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression. A prominent role in neuroprotection against excitotoxicity.  J Biol Chem. 1999;  274 6039-6042
    CrossrefPubMedGoogle Scholar
  • 8 D'Mello S R, Anelli R, Calissano P. Lithium induces apoptosis in immature cerebellar granule cells but promotes survival of mature neurons.  Exp Cell Res. 1994;  211 332-338
    CrossrefPubMedGoogle Scholar
  • 9 Ehrlich B E, Wright E M. Choline and PAH transport across the blood-brain barriers: The effect of lithium.  Brain Res. 1982;  250 245-249
    PubMedGoogle Scholar
  • 10 Ellman G L, Courtney K D, Andres V, Featherstone R M. A new and rapid colorimetric determination of acetylcholinesterase activity.  Biochem. Pharmac. 1961;  7 88-95
    CrossrefPubMedGoogle Scholar
  • 11 Evans M S, Zorumski C F, Clifford D B. Lithium enhances neuronal muscarinic excitation by presynaptic facilitation.  Neurosci. 1990;  38 457-468
    CrossrefPubMedGoogle Scholar
  • 12 Fonnum F. Radiochemical micro assay for the determination of choline acetyl-transferase and acetyl-cholinesterase activities.  Biochem J. 1969;  115 465-472
    PubMedGoogle Scholar
  • 13 Freeman S E, Dawson R M. Tacrine: A pharmacological review.  Prog Neurobiol. 1991;  36 257-277
    CrossrefPubMedGoogle Scholar
  • 14 Geoffroy M, Tvede K, Christensen A V, Schou J S. The effect of imipramine and lithium on “Learned helplessness” and acetylcholinesterase in rat brain.  Pharmacology Biochemistry & Behaviour . 1991;  38 93-97
    PubMedGoogle Scholar
  • 15 Jope R S. Effects of lithium treatment in vitro and in vivo on acetylcholine metabolism in rat brain.  J Neurochem. 1979;  33 -495
    PubMedGoogle Scholar
  • 16 Jope R S. Effects of lithium treatment in-vitro on acetylcholine metabolism in rat brain.  J Neurochem. 1983;  33 480-495
    PubMedGoogle Scholar
  • 17 Jope R S. Lithium selectively potentiates cholinergic activity in rat brain.  Progress in Brain Res. 1993;  98 317-322
    PubMedGoogle Scholar
  • 18 Jope R S. Anti-bipolar therapy: mechanisms of action of lithium.  Mol Psychiatry. 1999;  4 117-128
    CrossrefPubMedGoogle Scholar
  • 19 Jope R S, Morrisett R, Snead O C. Characterization of lithium potentiation of pilocarpine induced status epilepticus in rats.  Exp Neurol. 1986;  91 471-480
    CrossrefPubMedGoogle Scholar
  • 20 von der Kammer H, Mayhaus M, Albrecht C, Enderich J, Wegner M, Nitsch R M. Muscarinic acetylcholine receptors activate expression of the Egr gene family of transcription factors.  J Biol Chem. 1998;  273 14538-14544
    CrossrefPubMedGoogle Scholar
  • 21 Kaufer D, Friedman A, Seidman S, Soreq H. Acute stress facilitates long-lasting changes in cholinergic gene expression.  Nature. 1998;  393 373-377
    CrossrefPubMedGoogle Scholar
  • 22 Kling M A, Manowitz P, Pollack I W. Rat brain and serum lithium concentrations after acute injections of lithium carbonate and orotate.  J Pharm Pharmacol. 1978;  30 368-370
    PubMedGoogle Scholar
  • 23 Lehmann K. [Kinetics of lithium in the human organism]. [Article in German].  Int J Clin Pharmacol. 1974;  10 283-291
    PubMedGoogle Scholar
  • 24 Lehmann K, Scherber A, Graupner K. [Concentration course of lithium in liquor and aqueous humor after single oral application in man]. [Article in German].  Int J Clin Pharmacol Biopharm. 1976;  13 22-26
    PubMedGoogle Scholar
  • 25 Meyer E M, King M A, Meyers C. Neuroprotective effects of 2,4-dimethoxybenzylidene anabaseine (DMXB) and tetrahydroaminoacridine (THA) in neocortices of nucleus basalis lesioned rats.  Brain Res. 1998;  786 252-254
    CrossrefPubMedGoogle Scholar
  • 26 Morrisett R A, Jope R S, Snead O C. Status epilepticus is produced by administration of cholinergic agonists to lithium treated rats: comparison with kainic acid.  Exp Neurol. 1987;  98 594-605
    CrossrefPubMedGoogle Scholar
  • 27 Nanri M, Yamamoto J, Miyake H, Watanabe H. Protective effects of GTS-21, a novel nicotinic receptor agonist, on delayed neuronal death induced by ischemia in gerbils.  Jpn J Pharmacol. 1998;  76 23-29
    PubMedGoogle Scholar
  • 28 Nonaka S, Hough C J, Chuang D M. Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N-methyl-D-aspartate receptor-mediated calcium influx.  Proc Natl Acad Sci USA. 1998;  95 -2647
    PubMedGoogle Scholar
  • 29 O'Connell A, Earley B, Leonard B E. The neuroprotective effects of tacrine on trimethyltin induced memory and muscarinic receptor dysfunction in the rat.  Neurochem Int. 1994;  25 555-566
    CrossrefPubMedGoogle Scholar
  • 30 Pascual T, Gonzalez J-L. A protective effect of lithium on rat behaviour altered by ibotenic acid lesions of the basal forebrain cholinergic system.  Brain Res. 1995;  695 289-292
    CrossrefPubMedGoogle Scholar
  • 31 Paxinos G, Watson Ch. The rat brain in stereotaxic coordinates. Academic Press, New York 1986
    Google Scholar
  • 32 Peterson G L. A simplification of the protein assay method of Lowry et al., which is more generally applicable.  Analyt Biochem. 1977;  83 346-356
    CrossrefPubMedGoogle Scholar
  • 33 Sunaga K, Chuang D-M, Ishitani R. Tetrahydroaminoacridine is neurotrophic and promotes the expression of muscarinic receptor-coupled phosphoinositide turnover in differentiating cerebellar granule cells.  J. Pharmacology and Experimental Therapeutics. 1993;  264 463-486
    PubMedGoogle Scholar
  • 34 Svensson A L, Nordberg A. Tacrine interacts with an allosteric activator site on alpha 4 beta 2 nAChRs in M10 cells.  Neuroreport. 1996;  7 2201-2205
    PubMedGoogle Scholar
  • 35 Terhaag B, Scherber A, Schaps P, Winkler H. The distribution of lithium into cerebrospinal fluid, brain tissue and bile in man.  Int J Clin Pharmacol Biopharm. 1978;  16 333-335
    PubMedGoogle Scholar
  • 36 Yamada K, Saltarelli M D, Coyle J T. [3H] Hemicholinium-3 binding in rats with status epilepticus induced by lithium chloride and pilocarpine.  Eur J Pharmacol. 1991;  195 395-397
    CrossrefPubMedGoogle Scholar

Dr. Thomas Arendt

Paul Flechsig Institute of Brain Research Department Neuroanatomy University of Leipzig

Jahnallee 59

D-04109 Leipzig

Germany

eMail: aret@server3.medizin.uni-leipzig.de

      >