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Response: Comments on “Memantine Blocks α7* Nicotinic Acetylcholine Receptors More Potently Than N-Methyl-d-aspartate Receptors in Rat Hippocampal Neurons”

In the following reply, we would like to address point-bypoint the comments made by Banerjee et al. in response to our article entitled “Memantine Blocks 7* Nicotinic Acetylcholine Receptors More Potently than N-Methyl-D-aspartate Receptors in Rat Hippocampal Neurons” (J Pharmacol Exp Ther 312:1195–1205). The disclosure of this information will be extremely helpful for a better understanding of the outcomes of the clinical trials with memantine in different stages of Alzheimer’s disease (AD). The pathophysiology of AD is very complex and involves alteration of the amyloid precursor protein (APP) processing, excessive deposits of aggregates, excitotoxicity, and significant alterations in numerous neurotransmitter systems in the brain. Although the cause of AD remains undetermined, one of the most significant neuropathological hallmarks of the disease is the early development of nicotinic cholinergic deficits in the brain. Based on this knowledge, treatments presently approved by the Food and Drug Administration (FDA) for patients with mild-to-moderate AD include the cholinesterase inhibitors donepezil and rivastigmine, as well as galantamine, a drug that acts as a weak cholinesterase inhibitor and a nicotinic allosteric potentiating ligand (Doody, 2003). The N-methyl-D-aspartate (NMDA) receptor antagonist memantine is the only FDA-approved treatment for patients with moderate-to-severe AD (Reisberg et al., 2003). The ability of memantine to improve cognition in these patients seems to result from a selective inhibition of the excessive tonic NMDA receptor activity that accounts for the neurodegeneration observed in AD. In their comments, Banerjee et al. indicate that recent clinical studies have demonstrated beneficial effects of memantine in patients with mild-to-moderate AD. The clinical data from Peskind et al., which have been presented only in the format of research posters at the 17th Meeting of the American Association for Geriatric Psychiatry (Baltimore, MD; February 21–24, 2004) and the XXIV Collegium Internationale Neuro-Psychopharmacologicum Congress (Paris, France; June 20–24, 2004), has been recently reviewed in Areosa et al. (2004). Peskind et al. enrolled approximately 400 patients that had been diagnosed with mild-to-moderate AD and assigned these patients to treatment with memantine (20 mg/day) or placebo. At the end of the 24-week treatment, patients receiving memantine showed no significant improvements in the activities of daily living. Memantine caused an apparent small, albeit significant improvement in cognition, behavior, and mood, and the outcome of the clinician’s interview-based impression of change-plus caregiver input also favored memantine. However, the Cochrane Database Systematic Review of “Memantine on Dementia” reports the existence of two finished but unpublished clinical trials in which memantine failed to improve cognitive or global measures in patients with mild-to-moderate AD. Thus, at this point, we feel that the effects of memantine on mildto-moderate AD patients are unknown at best. Nevertheless, it has been reported that, based in part on results from Peskind et al., Forest Laboratories, Inc. intended to file a Supplemental New Drug Application with the FDA for approval of memantine for treatment of patients with mild-tomoderate AD (Rosack, 2004). These clinical findings and the presently available preclinical data on the inhibitory actions of memantine in the nicotinic cholinergic system in the brain (Buisson and Bertrand, 1998; Maskell et al., 2003; Aracava et al., 2005) suggest that the prospect of using this drug for treatment of mild-to-moderate AD should be examined with a great deal of awareness and caution. Although the authors state in their comments that 7 nAChR expression is relatively unaffected in AD regardless of the disease, there are plentiful reports of region-specific losses of 7 nAChRs in the AD brain (Banerjee et al., 2000; Perry et al., 2000; Court et al., 2001; Nordberg, 2001). In fact, the loss of 7 nAChRs is largely pronounced in the hippocampus of AD patients and not as significant in the cerebral cortex (Hellström-Lindahl et al., 1999; Wevers et al., 1999). It is also noteworthy that the degree of losses of cholinergic neurons and nAChRs (particularly 7 and 4 2) correlate well with the magnitude of cognitive decline in AD patients as the disease progresses from mild to moderate (Francis et al., 1985; Perry et al., 2000; Nordberg, 2001). In patients with more advanced stages of AD, such a correlation between nAChR loss and cognitive impairment does not seem to exist (Sabbagh et al., 2001). These findings support the clinical reports that nicotinic cholinergic enhancing therapies are more effective in patients with mild-to-moderate AD than in patients with moderate-to-severe AD (see Doody, 2003). There have been several reports that 7 nAChR agonists facilitate induction of long-term potentiation (LTP), a cellular mechanism believed to underlie learning and memory (Hunter et al., 1994; Fujii et al., 2000; Ji et al., 2001; He et al., 2003; Mann and Greenfield, 2003; Matsuyama and MatsuArticle, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.104.082222.