Comparison of donepezil-,tacrine-,rivastigmine-and metrifonateinduced central and peripheral cholinergically mediated responses in the rat

Abstract

There are now several acetylcholinesterase inhibitors in clinical use for the treatment of Alzheimer's disease, however, no systematic comparative studies of their central and peripheral cholinergic mediated effects in rats appear to have been reported. The present study investigated the dose–response characteristics of donepezil, tacrine, rivastigmine and metrifonate in inducing tremor, lacrimation, salivation and hypothermia and the duration of action of these compounds in Lister hooded rats. Data obtained were compared with the clinical observations on these drugs. Three doses of each compound were given orally to establish a dose–response curve for each behaviour, Tremor and lacrimation were scored, salivation was measured by weighing swabs applied to the mouth area and hypothermia was measured with a rectal probe. ED50 values were calculated for tremor. Using a just sub-maximal tremorigenic dose, the duration of response was examined. All four compounds produced dose–dependent increases in tremor and hypothermia. Only tacrine also produced marked salivation and lacrimation. The order of potency (ED50 value in µmol/kg) was rivastigmine (3.7), donepezil (18.0), tacrine (37.5), metrifonate (470). Tremor following tacrine (150 µmol/kg) and donepezil (20 µmol/kg) was prolonged (> 6 h) with a similar hypothermic response. The duration of these responses following metrifonate (777 µmol/kg) and rivastigmine (12.5 µmol/kg) did not exceed 3 h. Tacrine had poor selectivity for central (tremor) versus peripheral (salivation/lacrimation) effects compared to the other compounds. Donepezil also had a sustained duration of action. The data are consistent with clinical results and indicate that simple in-vivo models may assist in the selection of acetylcholinesterase inhibitors with a suitable response profile for use in the symptomatic treatment of Alzheimer's disease.

Keywords

acetylcholinesterase inhibitors cholinergically mediated behaviour donepezil metrifonate rivastigmine salivation tacrine tremor

Get full access to this article

View all access options for this article.

References

Blokland A (1996) Acetylcholine: a neurotransmitter for learning and memory? Brian Res Rev 21: 285–300

Davies P , Maloney A F J (1976) Selective loss of central cholinergic neurons in Alzheimer's disease. Lancet 2: 1403-1403

Enz A, Floersheim P (1996) Cholinesterase inhibitors: an overview of their mechanism of action. In Becker R , Giacobini E (eds), Alzheimer's disease: from molecular biology to therapy. Birkhauser, Boston, MA, pp. 211–215

Francis P T , Palmer A M , Sims N R , Bowen D M , Davison A N , Esiri M N , Neary M D , Snowden J S , Wilcox G K (1985) Neurochemical studies of early onset Alzheimer's disease – possible influences on treatment. New Engl J Med 313: 7–11

Giacobini E , Zhu X, Williams E , Sherman K A (1996) The effect of acetylcholinesterase inhibitor E2020 on extracellular acetylcholine and biogenic amine levels in rat cortex Neuropharmacology 35: 205–211

Hunter A J , Murray T K , Jones J A , Cross A J , Green A R (1989) The cholinergic pharmacology of tetrahydroaminoacridine in vivo and in vitro. Br J Pharmacol 98: 79–88

Itoh A, Nitta A , Katono Y , Usui M , Naruhashi K , Iida R , Hasegawa T , Nabeshima T (1997) Effects of metrifonate on memory impairment and cholinergic dysfunction in rats. Eur J Pharmacol 322: 11–19

Nordberg, A , Svensson A L (1998) Cholinesterase inhibitors in the treatment of Alzheimer's disease, a comparison of tolerability and pharmacology. Drug Safety 19: 465–480

Nordgren I , Bergstrom M , Holmstedt B , Sandoz M (1978) Transformation and action of metrifonate. Arch Toxicol 41: 31–41

10.

Sanchez C , Lembol H L (1994) The involvement of muscarinic receptor subtypes in the mediation of hypothermia, tremor and salivation in male mice. Pharmacol Toxicol 74: 35–39

11.

Sanchez C , Meier E (1993) Central and peripheral mediation of hypothermia, tremor and salivation mediated by muscarinic agonists in mice. Pharmacol Toxicol 73: 262–267

12.

Snape M F , Misra A , Murray T K , De Souza R J , Williams J L , Cross A J , Green A R (1999) A comparative study in rats of the in vitro and in vivo pharmacology of the acetylcholinesterase inhibitors tacrine, donepezil and NXX-066. Neuropharmacology 38: 181–193

13.

Sugimoto H , Tsuchiya Y , Higurashi K , Karibe N , Limura Y , Sasaki A , Yamanashi Y , Ogura H , Arabi S , Kosasa T , Kusota A , Kozasa M , Yamatsu K (1988) Cyclic amine compounds, its use and pharmaceutical composition comprising it. European Patent 296 560 A2-A2 (Eisai Co. Ltd)

14.

van der Staay F J , Hinz V C , Schmidt B H (1996) Effects of dimetrifonate, its transformation product dichlorvos, and other organophosphorus and reference cholinesterase inhibitors on Morris water escape behavior in young adult rats. J Pharmacol Exp Ther 278: 697–708