Co-administration of Memantine with Acetylcholinesterase Inhibitors: Preclinical and Clinical Evidence
Pathogenesis of Alzheimer’s disease (AD) as a neurodegenerative disease involves more than one mechanism. Multiple studies in the last two decades revealed degeneration of cholinergic nuclei localized in the basal forebrain to occur in the course of this disease. Impairment of the cholinergic system which projects into large areas of the limbic system and the neocortex is followed by disturbance of attentional processes and cognitive decline (Terry and Buccafusco 2003). Consistent with these findings, some compounds increasing cholinergic neurotransmission were found effective in AD. Of various cholinomimetic drug classes, only reversible acetylcholinesterase (AChE) inhibitors have been successfully used in AD patients (for review see Ibach and Haen 2004). The first compounds of this class tested in the clinical trials were physostigmine (Stern et al., 1988; Thal et al., 1989) and tacrine (Summers et al., 1986). However, because of the short duration of action of the former and hepatotoxicity of the latter drug, their use in AD patients has been largely abandoned (Ibach and Haen 2004). Tacrine was the first drug approved specifically for the treatment of AD (1993). This was followed by the development of compounds with improved specificity and tolerability: donepezil (1996), rivastigmine (2000), and most recently galantamine (2001).
Aside from the cholinergic hypothesis, it is generally agreed that compromised neuronal energy metabolism may occur in AD. Continuous mild activation of N-methyl-D-aspartate (NMDA) receptors under such conditions may render the cells susceptible to subsequent damage. Indeed, the NMDA antagonist memantine was shown efficient in animal models relevant to human neurodegenerative diseases and dementia. Preclinical studies in vitro and in vivo showed that such a non-contingent activation of this receptor type also leads to impairment of neuronal plasticity (learning) which can be restored by therapeutic concentrations of memantine (Danysz & Parsons 2003). These preclinical results were further confirmed in multiple clinical trials. Recently, memantine has been approved by the Food and Drug Administration as the first drug for moderate-to-severe AD and is also available in Europe. After the anti-dementia potential of memantine had been widely acknowledged, it became obvious that possible effects of co-administration of this drug with the clinically available AChE inhibitors would soon be under investigation. The present chapter is aimed at presenting the preclinical and clinical profile of memantine and at discussing results of animal and human studies on its coadministration with various classes of AChE inhibitors.
