Donepezil is the common standard symptomatic treatment for mild-to-moderate Alzheimer's disease (AD) patients, but it showed only moderate efficacy and also emergence tolerance. To conquer this shortcoming, combinations of several drugs are widely used. Statins, competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, are commonly prescribed drugs for the treatment of hypercholesterolemia. Growing evidence demonstrated that this class of medicines exerts neuroprotective effects in neurological disorders, including AD. We have examined whether co-administration of lovastatin with donepezil provides a synergistic cognition-improving effect in an animal model of AD. In rats with the bilaterally lesioned nucl. basalis magnocellularis (NBM), lovastatin (20 mg/kg) and donepezil (10 mg/kg), when administered separately, noticeably improved working and reference memory tests in the radial maze, compared to the NBM lesioned group with no treatment but not with lower doses. Combined administration of subtherapeutic doses of lovastatin (1.0 mg/kg) and donepezil (0.1 mg/kg), which exerted no discernible effects on performance when given alone, significantly improved working and reference memory, indicating a synergistic cognitionimproving effect. This result suggests that a low dose of lovastatin potentiates the effect of an inactivedose of donepezil on cognitive impairment, and that the synergistic effect may be mediated through increases in the choline acetyltransferase activity and ACh level to compensate the cholinergic deficit in the rat model of Alzheimer's disease.
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