Abstract This review describes the preclinical mecha- nisms that may underlie the increased therapeutic benefit of combination therapy—with the N-methyl-D-aspartate receptor antagonist, memantine, and an acetylcholinesterase inhibitor (AChEI)—for the treatment of Alzheimer’s disease (AD). Memantine, and the AChEIs target two different aspects of AD pathology. Both drug types have shown sig- nificant efficacy as monotherapies for the treatment of AD. Furthermore, clinical observations indicate that their com- plementary mechanisms offer superior benefit as combina- tion therapy. Based on the available literature, the authors have considered the preclinical mechanisms that could underlie such a combined approach. Memantine addresses dysfunction in glutamatergic transmission, while the AC- hEIs serve to increase pathologically lowered levels of the neurotransmitter acetylcholine. In addition, preclinical C. G. Parsons In Vitro Pharmacology, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318 Frankfurt, Germany C. G. Parsons (&) In Vitro Pharmacology, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318 Frankfurt, Germany e-mail: firstname.lastname@example.org W. Danysz A. Dekundy In Vivo Pharmacology, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318 Frankfurt, Germany e-mail: email@example.com A. Dekundy e-mail: firstname.lastname@example.org I. Pulte Global Clinical Research and Development CNS, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318 Frankfurt, Germany e-mail: email@example.com studies have shown that memantine has neuroprotective effects, acting to prevent glutamatergic over-stimulation and the resulting neurotoxicity. Interrelations between the glutamatergic and cholinergic pathways in regions of the brain that control learning and memory mean that combi- nation treatment has the potential for a complex influence on disease pathology. Moreover, studies in animal models have shown that the combined use of memantine and the AChEIs can produce greater improvements in measures of memory than either treatment alone. As an effective approach in the clinical setting, combination therapy with memantine and an AChEI has been a welcome advance for the treatment of patients with AD. Preclinical data have shown how these drugs act via two different, but interconnected, pathological pathways, and that their complementary activity may pro- duce greater effects than either drug individually.
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