Reversal of scopolamine-induced deficits in radial maze performance by (−)-huperzine A: comparison with E2020 and tacrine
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;
References (25)
- et al.
Processes of verbal memory failure in Alzheimer-type dementia
Brain Cogn.
(1985) - et al.
Scopolamine impairs both working and reference memory in rats: a replication and extension
Pharmacol. Biochem. Behav.
(1989) - et al.
Interaction of 9-amino-1,2,3,4-tetrahydroaminoacridine (THA) with human cortical nicotinic and muscarinic receptor binding in vitro
Neurosci. Lett.
(1988) - et al.
Effects of scopolamine on radial maze performance in rats
Physiol. Behav.
(1981) - et al.
Differential effects of scopolamine on working and reference memory of rats in the radial maze
Pharmacol. Biochem. Behav.
(1984) - et al.
The decline of working memory in Alzheimer's disease
Brain
(1991) - et al.
Short-term memory in the rhesus monkey: disruption from the anti-cholinergic scopolamine
Pharmacol. Biochem. Behav.
(1976) - et al.
The cholinergic hypothesis of geriatric memory dysfunction
Science
(1982) - Becker, R.E., Moriearty, P., Unni, L., 1991. The second generation of cholinesterase inhibitors: clinical and...
- Brufani, M., Filocamo, L., 1996. Rational design of new acetylcholineterase inhibitors, In: Becker, R., Giacobini, E....
Comparative behavioral and neurochemical activities of cholinergic antagonists in rats
J. Pharmacol. Exp. Ther.
Cited by (86)
Evaluation of bioactive compounds as AChE inhibitors from medicinal plants
2022, Evidence-Based Validation of Herbal Medicine: Translational Research on BotanicalsPyridine alkaloids with activity in the central nervous system
2020, Bioorganic and Medicinal ChemistryCitation Excerpt :Tang and co-workers demonstrated that both working and reference memory deficits induced by scopolamine (a mAChR antagonist commonly used to induce cognitive deficits) were significantly improved upon huperzine A administration.106,108,118 The improvements were more pronounced on working memory than on reference memory.118 Upon oral administration to aged rats, huperzine A was ~3.5 and 9-fold more potent at ameliorating memory impairments than donepezil and tacrine respectively, in agreement with the results reported by Tang and co-workers.115
The pharmacology of tacrine at N-methyl-D-aspartate receptors
2017, Progress in Neuro-Psychopharmacology and Biological PsychiatryEvaluation of Bioactive Compounds as Acetylcholinesterase Inhibitors from Medicinal Plants
2015, Evidence-Based Validation of Herbal Medicine