Reversal of scopolamine-induced deficits in radial maze performance by (−)-huperzine A: comparison with E2020 and tacrine

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Abstract

The effects of (−)-huperzine A ((5R,9R,11E)-5-amino-11-ethylidene- 5,6,9,10-tetrahydro-7-methyl-5,9-methanocycloocta[b]pyridin-2(1H)-one), and of the hydrochloride salt of E2020 ((R,S)-1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methyl piperidine) and tacrine (9-amino-1,2,3,4-tetrahydroacridine), on the scopolamine-induced memory deficits in rats were compared in a radial maze, using a 4-out-of-8 baiting procedure. Scopolamine (0.15 mg/kg, i.p.) caused significant impairment in the rats' ability to fulfil the radial maze task. (−)-Huperzine A (0.2–0.4 mg/kg, p.o.; 0.1–0.4 mg/kg, i.p.) had greater efficacy than E2020 (0.6–0.9 mg/kg, p.o.; 0.3–0.6 mg/kg, i.p.) and tacrine (1.5–2.5 mg/kg, p.o.; 0.3–0.6 mg/kg, i.p.) on the improvement of scopolamine-induced working and reference memory errors, respectively. There appeared to be an inverse bell-shape dose-dependent effect for all three compounds tested. The compared data demonstrate that (−)-huperzine A is the most potent and orally active acetylcholinesterase inhibitor of the three, and fits more closely the established criterions for an ideal acetylcholinesterase inhibitor to be used in clinical studies.

Introduction

It is generally accepted that a cholinergic neural deficit is one of the main neurotransmitter-related deficits found in Alzheimer's disease which is characterised by a progressive loss of the memory function (Deutsch, 1971; Bartus et al., 1982; Coyle et al., 1983). In humans, changes in cognitive processes induced by the blockade of cholinergic activity have been associated with impaired attention and inability to store new information (Rusted, 1994). It has been reported that, using spatial tasks, cholinergic blockade results in specific impairments in both working and reference memory in rats (Watts et al., 1981). So far, cholinesterase inhibitors are the most popular strategies for increasing cholinergic activity in the brain, and show the most encouraging results as palliative therapy for Alzheimer's disease (Brufani and Filocamo, 1996). Among the inhibitors, physostigmine and tacrine have been evaluated on a large scale in Alzheimer's disease. They are not, however, the ideal drugs for clinical use because of their narrow therapeutic window, low bioavailability, and dose-dependent hepatotoxicity, especially of tacrine (Marx, 1987; Watkins et al., 1994). Therefore, it seems necessary to continue to seek for new cholinesterase inhibitors with markedly reduced side-effects and greater therapeutic window than those of the drugs tested.

Thus, there is now a more available new generation of acetylcholinesterase inhibitors, (−)-huperzine A and E2020, with minimal toxicity. (−)-Huperzine A, a novel natural Lycopodium alkaloid, was originally extracted from Chinese clubmoss, Huperzia serrata, with unique anti-acetylcholinesterase potency and pharmacokinetic properties (Tang, 1996). E2020, a specific piperidine-based acetylcholinesterase inhibitor, had a long duration of inhibitory action and was devoid of unexpected toxicity in the initial clinical studies (Rogers et al., 1991).

Previous studies with (−)-huperzine A and E2020 have suggested their improved abilities to overcome the problems associated with the use of physostigmine and tacrine. Thus, the present study aimed to provide comparative data on (−)-huperzine, E2020, and tacrine by testing their nootropic effects on scopolamine-induced amnesia—a widely cited model for human dementia in general and for Alzheimer's disease in particular (Drachman and Leavitt, 1974; Bartus and Johnson, 1976; Ober et al., 1985; Baddeley et al., 1991).

Section snippets

Subjects

Fifty experimentally naive male albino rats of the Sprague–Dawley strain (from the Experimental Animal Central of Shanghai, Chinese Academy of Sciences) weighing 220–270 g were housed individually in a climate-controlled room under a reversed 12 h light–dark cycle (lights off: 0830). All treatments and behavioural testing were performed during the dark period of the light–dark cycle when the rats were normally most active. The rats were allowed access to water ad libitum and a standard diet to

Acquisition

The acquisition of the working and reference memory components of the radial arm maze task on Weeks 1–8 is presented in Fig. 1. It took fewer weeks for the acquisition of the working memory component (3 to 4 weeks) to reach a relatively stable level of about 0.1 errors per rat each session than for acquisition of the reference memory component (7 to 8 weeks) of about 0.3 errors per rat each session. We trained rats to this criterion to decrease baseline error rates, which is permitting the

Discussion

The partially baited radial maze, due to its close resemblance to the natural food-seeking conditions for species such as rats, is widely used in the study of drug effects on spatial memory. A muscarinic acetylcholine receptor antagonist, scopolamine, that is widely accepted as providing a model of cognitive deficits in experimental animals, has been extensively used as a preclinical tool to test the efficacy of new drugs which may have cognition-enhancing potential (Bymaster et al., 1993;

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