The N-butylcarbamate derivative of galantamine acts as an allosteric potentiating ligand on alpha7 nicotinic receptors in hippocampal neurons: clinical implications for treatment of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairments that become severe enough to interfere with the daily activities of patients and eventually lead to death (Chung and Cummings, 2000). Arecent study reports that approx 24 million people suffer from dementia worldwide. If the mortality rate does not change and no curative or preventive treatment is developed, this number is expected to double every 20 yr worldwide (Ferri et al., 2005). Although the causes of AD remain obscure, it has been reported that incremental loss of cholinergic neurons and of nicotinic receptor (nAChR) function/expression in specific brain regions correlates well with the severity of the symptoms at early stages of the disease (Hellström-Lindahl et al., 1999; Nordberg, 2001; Perry et al., 2001; Wevers et al., 1999). In patients with more advanced stages of AD, such a correlation between the magnitude of nAChR loss and of cognitive decline does not appear to exist (Sabbagh et al., 2001). The nicotinic cholinergic system plays a central role in modulating different forms of associative learning known to be impaired in AD patients, including the eyeblink classical conditioning (Woodruff-Pak, 2001), and in maintaining neuronal viability. Neuroprotection and cognitive improvement result from increasing the activity of different nAChR subtypes, including those bearing the alpha7 subunit (Carlson et al., 1998; Hejmadi et al., 2003; Kihara et al., 1997; Levin et al., 2006). Thus, increasing nAChR activity in the brain was proposed as a mechanism to slow down the progression of the disease (Maelicke and Albuquerque, 1996).