Modulation of N-Methyl-d-aspartate Receptors by Donepezil in Rat Cortical Neurons

Abstract

Nicotinic acetylcholine receptors and N-methyl-D-aspartate (NMDA) receptors are known to be down-regulated in the brain of patients with Alzheimer's disease. It was previously shown that the nootropic drugs nefiracetam and galantamine potentiate the activity of both nicotinic and NMDA receptors. We hypothesized that donepezil, a nootropic with a potent anticholinesterase activity, might also affect the NMDA system. NMDA-induced currents were recorded from rat cortical neurons in primary culture using the whole-cell patch-clamp technique at a holding potential of Ϫ70 mV in Mg 2ϩ -free solutions. In multipolar neurons, NMDA currents were decreased by bath and U-tube applications of 1 to 10 M donepezil but were increased by 30 to 100 M donepezil. Donepezil suppression occurred in a manner independent of NMDA concentrations ranging from 3 to 1000 M. The donepezil suppression of NMDA currents was prevented by inhibition of protein kinase C (PKC) but unaffected by protein kinase A (PKA) and G proteins. In bipolar neurons, however, NMDA currents were potently augmented by bath and U-tube applications of 0.01 to 100 M donepezil. Donepezil potentiation occurred at high NMDA concentrations that evoked the saturating responses and in a manner independent of NMDA concentrations ranging from 3 to 1000 M. The potentiation of NMDA currents by donepezil was decreased by inhibition of PKC and abolished by modulation of G proteins but not by PKA inhibition. It was concluded that donepezil at low therapeutic concentrations (0.01-1 M) potentiated the activity of the NMDA system and that this action together with cholinesterase inhibition would contribute to the improvement of learning, memory, and cognition in patients with Alzheimer's disease.

Cognitive evaluation of disease-modifying efficacy of donepezil in the APP23 mouse model for Alzheimer’s disease

“…It has been suggested that most AChE inhibitors available antagonize cerebral NMDA receptors with a potency of approximately three orders of magnitude lower than their action on AChE activity Moriguchi et al 2005;Muñez-Torrero and Camps 2006;Takada-Takatori et al 2006). Therefore, a possible beneficial effect of donepezil based on inhibition of excitotoxicity should be considered.…”

Galantamine and donepezil attenuate pharmacologically induced deficits in prepulse inhibition in rats

“…The basis of the differential effects of the compounds observed in our studies and the one cited above is unclear, although there are some differences in the pharmacology of these compounds (i.e., other than that related to AChEI activity) that may be of importance. For example, in culture studies, galantamine, has been observed to potentiate NMDA currents in rat cortical multipolar neurons (Moriguchi et al, 2005). In contrast, donepezil, potentiated NMDA receptors in both bipolar and multipolar neurons, but its effects on multipolar neurons were biphasic.…”

Combination of Rimonabant and Donepezil Prolongs Spatial Memory Duration

“…Systemic administration of donepezil has been found to increase levels of norepinephrine, dopamine, and serotonin, in addition to its effects on acetylcholine (Cuadra et al, 1994;Giacobini et al, 1996;Shearman et al, 2006). Donepezil also has been shown to potentiate NMDAinduced currents in multipolar and bipolar neurons (Moriguchi et al, 2005), as well as to produce NMDA receptor blockade and have agonist-like activity at sigma receptors (Maurice et al, 2006). Rimonabant is thought to produce its effects by either antagonizing a tonically active endogenous cannabinoid system or through its actions as an inverse agonist (Landsman et al, 1997).…”

“…Specifically, it has been suggested that mechanisms other than enhancement of cholinergic function may be involved in the pharmacology of donepezil efficacy in improving cognition (Narahashi et al, 2004;Moriguchi et al, 2005). Systemic administration of donepezil has been found to increase levels of norepinephrine, dopamine, and serotonin, in addition to its effects on acetylcholine (Cuadra et al, 1994;Giacobini et al, 1996;Shearman et al, 2006).…”