nach oben

Drugs & Aging

Erschienen in:

01.12.2001 | Leading Article

Selective Inhibitors of Butyrylcholinesterase

A Valid Alternative for Therapy of Alzheimer’s Disease?

verfasst von: Dr Ezio Giacobini

Erschienen in: Drugs & Aging | Ausgabe 12/2001

Einloggen, um Zugang zu erhalten

Abstract

The brain of mammals contains two major forms of cholinesterases (ChEs): acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The two forms differ genetically, structurally and in their kinetics. Butyrylcholine is not a physiological substrate in mammalian brains which makes the function of BuChE difficult to interpret. In human brains, BuChE is found in neurons and glial cells as well as in neuritic plaques and tangles in patients with Alzheimer’s disease (AD).While AChE activity decreases progressively in the brain of patients with AD, BuChE activity shows some increase.

In order to study the function of BuChE, we perfused intracortically the rat brain with a selective BuChE inhibitor. We found that extracellular acetylcholine levels increased 15-fold from 5 nmol/L to 75 nmol/L concentrations, with little cholinergic adverse effect in the animal. Based on these data, we postulated that two pools of ChEs may be present in the brain: one mainly neuronal and AChE dependent; and one mainly glial and BuChE dependent. The two pools show different kinetic properties with regard to regulation of acetylcholine concentration in the brain and can be separated with selective inhibitors.

The recent development of highly selective BuChE inhibitors will allow us to test these new agents in patients with AD in order to find out whether or not they represent an advantage for the treatment of patients with AD as compared with selective (donepezil) or relatively non-selective (rivastigmine, galantamine) ChE inhibitors presently in use.

The association between a BuChE-K variant and AD has not been confirmed in several studies.

In conclusion, additional experimental and clinical work is necessary in order to elucidate the role of BuChE in normal brain function and in the brains of patients with AD. In the future, it may be possible that selective BuChE inhibitors will have a role in treatment of patients with advanced AD.

Silver A. The biology of cholinesterases. Amsterdam: Elsevier, 1974: 426–47

Giacobini E, Holmstedt B. Cholinesterase content of certain regions of the spinal cord as judged by histochemical and cartesian diver technique. Acta Physiol Scand 1958; 42: 12–27PubMedCrossRef

Giacobini E. Distribution and localization of cholinesterases in nerve cells. Acta Physiol Scand 1959; 45 Suppl. 156: 1

Giacobini E. Metabolic relations between glia and neurons studied in single cells. In: Maynard M, Cohen MD, Snider R, editors. Morphological and biochemical correlates of neural activity. New York: Harper & Row, 1964: 15–38

Wright CI, Geula C, Mesulam MM. Neurological cholinesterases in the normal brain and in Alzheimer’s disease: relationship to plaques, tangles and patterns of selective vulnerability. Ann Neurol 1993; 34: 373–84PubMedCrossRef

Perry EK, Perry RH, Blessed G, et al. Changes in brain cholinesterases in senile dementia of Alzheimer type. Neuropathol Appl Neurobiol 1978; 4: 273–7PubMedCrossRef

Arendt T, Bruckner MK, Lange M, et al. Changes in acetylcholinesterase and butyrylcholinesterase in Alzheimer’s disease resemble embryonic development — a study of molecular forms. Neurochem Int 1992; 21(3): 381–96PubMedCrossRef

Davies P. Neurotransmitter-related enzymes in senile dementia of the Alzheimer type. Brain Res 1979; 171: 319–27PubMedCrossRef

Atack JR, Perry EK, Bonham JR, et al. Molecular forms of butyrylcholinesterase in the human neocortex during development and degeneration of the cortical cholinergic system. J Neurochem 1987; 48(6): 1687–92PubMedCrossRef

10.

Atack JR, Perry EK, Bonham JR, et al. Molecular forms of acetylcholinesterase and butyrylcholinesterase in the aged human central nervous system. J Neurochem 1986; 47(1): 263–77PubMedCrossRef

11.

Arendt T, Bruckner M, Lange M, et al. Changes in acetylcholinesterase and butyrylcholinesterase in Alzheimer’s disease resemble embryonic development — a study of molecular forms. J Neurochem 1992; 21(3): 231–44

12.

Giacobini E, DeSarno P, Clark B, et al. The cholinergic receptor system of the human brain — neurochemical and pharmacological aspects in aging and Alzheimer. In: Nordberg A, Fuxe K, Holmstedt B, editors. Progress in brain research. Amsterdam: Elsevier, 1989: 335–43

13.

Giacobini E. Cholinesterase inhibitors: from the Calabar bean to Alzheimer therapy. In: Giacobini E, editor. Cholinesterases and cholinesterase inhibitors. London: Martin Dunitz, 2000: 181–226

14.

Sussman JL, Harel M, Farlow F, et al. Atomic structure of acetylcholinesterase from Torpedo Californica: a prototypic binding protein. Science 1991; 253(5002): 872–9PubMedCrossRef

15.

Vellom DC, Radie Z, Li Y, et al. Amino acid residues controlling acetylcholinesterase and butyrylcholinesterase specificity. Biochemistry 1993; 32(1): 12–7PubMedCrossRef

16.

Shafferman A, Velan B, Ordentlich A, et al. Substrate inhibition of acetylcholinesterase: residues affecting signal transduction from the surface to the catalytic center. EMBO J 1992; 11(10): 3561–8PubMed

17.

Iyo M, Namba H, Fukushi K, et al., Measurement of acetylcho linesterase by positron emission tomography in the brains of healthy controls and patients with Alzheimer’s disease. Lancet 1997; 349: 1805–9PubMedCrossRef

18.

Perry EK, Tomlison BE, Blessed G, et al. Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. BMJ 1978; II: 1457–9CrossRef

19.

Mesulam MM, Geula C. Butyrylcholinesterase reactivity differentiates the amyloid plaques of aging from those of dementia. Ann Neurol 1994; 36(5): 722–7PubMedCrossRef

20.

Inestrosa NC, Alvarez A, Godoy J, et al. Acetylcholinesteraseamyloid-beta-peptide interaction and Wnt signaling involvement in neurotoxicity. Acta Neurol Scand 2000; 102: 1–7CrossRef

21.

Ogane N, Giacobini E, Messamore E. Preferential inhibition of acetylcholinesterase molecular forms in rat brain. Neurochem Res 1992; 17(5): 489–95PubMedCrossRef

22.

Ogane N, Giacobini E, Struble R. Differential inhibition of acetylcholinesterase molecular forms in normal and Alzheimer disease brain. Brain Res 1992; 17(5): 307–12CrossRef

23.

Giacobini E, Griffini PL, Maggi T, et al. The effect of MF8622, a selective butyrylcholinesterase inhibitor on cortical levels of acetylcholine [abstract]. Society for Neuroscience Annual Meeting; 1995 Nov 11–16; San Diego (CA)

24.

Cuadra G, Summers K, Giacobini E. Cholinesterase inhibitor effects on neurotransmitters in rat cortes in vivo. J Pharmacol Exp Ther 1994; 270(1): 277–84PubMed

25.

Cuadra G, Giacobini E. Coadministration of Cholinesterase inhibitors and idazoxan: effects of neurotransmitters in rat cortex in vivo. J Pharmacol Exp Ther 1995; 273: 230–40PubMed

26.

Massoulié J, Toutant JP. Vertebrates ChEs: structure and types of interaction. Chapter 86. In: Whittaker VP, editor. Handbook of experimental pharmacology. Berlin-Heidelberg: Springer Verlag, 1988: 167–224

27.

Yu Q, Holloway HW, Utsuki T, et al. Synthesis of novel phenser-ine-based selective inhibitors of butyrylcholinesterase for Alzheimer’s disease. J Med Chem 1999; 42(10): 1855–61PubMedCrossRef

28.

Greig NH, Utsuki T, Yu Q, et al. Butyrylcholinesterase: a new therapeutic target in Alzheimer’s disease treatment? Alz Insights 2001; 7(2): 1–4

29.

Yu GS, Holloway HW, Flippen-Anderson F, et al. Methyl analogues of the experimental Alzheimer’s drug phenserine: synthesis and structure-activity relationship for acetyl- and butyrylcholinesterase inhibitory action. J Med Chem 2001; 38: 198–221

30.

Lahiri DK, Farlow MR, Hintz N, et al. Cholinesterase inhibitors, beta amyloid precursor protein and amyloid beta-pep-tides in Alzheimer’s disease. Acta Neurol Scand 2000; 102: 60–7CrossRef

31.

Shaw KTY, Utsuki T, Rogers J, et al. Phenserine regulates translation of B-amyloid precursor protein mRNA by a putative interleukin-1 responsive element: a target for drug development. Proc Nat Acad Sci USA 2001; 98: 7605–10PubMedCrossRef

32.

Haroutunian V, Ahlers SA, Greig NH, et al. Induction, secretion and pharmacological regulation of beta-APP in animal model systems. In: Fisher A, Yoshida M, Hanin I, editors. Progress in Alzheimer’s and Parkinson’s disease. New York: Plenum, 1997

33.

Costa J, Anand R, Cutler N, et al. Correlation between cognitive effects and level of acetylcholinesterase inhibition in a trial of rivastigmine in Alzheimer’s patients [poster NR 561]. American Society of Psychiatry Annual Meeting; 1999; Chicago (IL)

34.

Lehmann DJ, Johnston C, Smith AD. Synergy between the genes for butyrylcholinesterase K variant and apolipoprotein E 4 in late-onset confirmed Alzheimer’s disease. Hum Mol Genet 1997; 6(11): 1933–6PubMedCrossRef

35.

Tilley L, Morgan K, Grainger J, et al. Evaluation of polymorphism in the presenilin-1 gene and the butyrylcholinesterase gene as risk factors in sporadic Alzheimer’s disease. Eur J Hum Genet 1999; 7(6): 659–63PubMedCrossRef

36.

Meilroy SP, Crawford VLS, Dynan KB, et al. Butyrylcholinesterase k variant is genetically associated with late onset Alzheimer’s disease in Northern Ireland. J Med Genet 2000; 37(3): 182–5CrossRef

37.

Panegyres PK, Mamotte CDS, Vasikaran SD, et al. Butyrylcholinesterase K variant and Alzheimer’s disease. J Neurol 1999; 246(5): 369–70PubMedCrossRef

38.

Singleton AB, Gibson AM, Edwarson JA. Butyrylcholinesterase K: an association with dementia with Lewy bodies. Lancet 1998; 351: 1818PubMedCrossRef

39.

Kehoe PG, Williams H, Holmans P, et al. The butyrylcholinesterase K variant and susceptibility to Alzheimer’s disease. J Med Genet 1998; 35(12): 17201CrossRef

40.

Russ C, Powell J, Lovestone S, et al. K variant of butyrylcholinesterase and late-onset Alzheimer’s disease. Lancet 1998; 351:881PubMedCrossRef

41.

Yamamoto Y, Yasuda M, Mori E, et al. Failure to confirm a synergistic effect between the K-variant of the butyrylcholinesterase gene and the epsilon 4 allele of the apolipoprotein gene in Japanese patients with Alzheimer’s disease. J Neurol Neurosurg Psychiatry 1999; 67(1): 94–6PubMedCrossRef

42.

Grubber JM, Saunders AM, Cranegatherum AR, et al. Analysis of association between Alzheimer’s disease and the K variant of butyrylcholinesterase. Neurosci Lett 1999; 269(2): 115–9PubMedCrossRef

43.

Lee DW, Liu HC, Chi C, et al. No association between butyrylcholinesterase K-variant and Alzheimer’s disease in Chinese. Am J Med Genet 2000; 96(2): 167–9PubMedCrossRef

44.

Yamamoto Y, Sengo M, Yasuda M, et al. No association between Presinilin 1 Intron gene or Butyrylcholinesterase K variant and Alzheimer’s disease in Japanese populations. Psychogeriatrics 2001; 1(1): 108–18CrossRef

45.

Yamada M, Sodeyama N, Itoh Y, et al. Butyrylcholinesterase K variant and cerebral amyloid angiopathy. Stroke 1998; 29(12): 2488–90PubMedCrossRef

46.

Greig NH, Utsuki T, Yu QS, et al. A new therapeutic target in Alzheimer’s disease treatment: attention to butyrylcholinesterase. Curr Med Res Opin 2001; 17(3): 1–7

47.

Ballard, CG. Advances in the treatment of Alzheimer’s disease: benefits of dual Cholinesterase inhibition. Eur Neurol 2001; 46(4): 136–42

Titel: Selective Inhibitors of Butyrylcholinesterase
A Valid Alternative for Therapy of Alzheimer’s Disease?
verfasst von: Dr Ezio Giacobini
Publikationsdatum: 01.12.2001
Verlag: Springer International Publishing
Erschienen in: Drugs & Aging / Ausgabe 12/2001
Print ISSN: 1170-229X
Elektronische ISSN: 1179-1969
DOI: https://doi.org/10.2165/00002512-200118120-00001

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

26.04.2024 Hüft-TEP Nachrichten

Ob bei einer Notfalloperation nach Schenkelhalsfraktur eine Hemiarthroplastik oder eine totale Endoprothese (TEP) eingebaut wird, sollte nicht allein vom Alter der Patientinnen und Patienten abhängen. Auch über 90-Jährige können von der TEP profitieren.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Bei schweren Reaktionen auf Insektenstiche empfiehlt sich eine spezifische Immuntherapie

25.04.2024 Allergien und Intoleranzreaktionen Nachrichten

Insektenstiche sind bei Erwachsenen die häufigsten Auslöser einer Anaphylaxie. Einen wirksamen Schutz vor schweren anaphylaktischen Reaktionen bietet die allergenspezifische Immuntherapie. Jedoch kommt sie noch viel zu selten zum Einsatz.

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

25.04.2024 Hypertonie Nachrichten

Beginnen ältere Männer im Pflegeheim eine Antihypertensiva-Therapie, dann ist die Frakturrate in den folgenden 30 Tagen mehr als verdoppelt. Besonders häufig stürzen Demenzkranke und Männer, die erstmals Blutdrucksenker nehmen. Dafür spricht eine Analyse unter US-Veteranen.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 12/2001

Cytomegalovirus and the Aging Population

Progressive Supranuclear Palsy

Tegafur/Uracil

Oral Tegafur/Uracil