Several drugs are in clinical use for symptomatic treatment of Alzheimer's disease patients. Since Alzheimer's disease is known to be associated with down-regulation of the cholinergic and N-methyl-D-aspartate (NMDA) systems, most of these drugs inhibit acetylcholinesterase, potentiate the activity of nicotinic acetylcholine receptors (nAChRs), or modulate NMDA receptors. Galantamine is an anticholinesterase and allosterically potentiates the activity of the nicotinic receptors. We have recently found that galantamine potentiates the activity of NMDA receptors as well. Memantine is unique in that it inhibits the NMDA receptors. We have developed a hypothesis that combining galantamine and memantine will be more effective for improving the patient's conditions than monotherapy with either drug. Patch clamp and intracellular Ca(2+) imaging experiments using rat cortical and hippocampal neurons clearly provided the in vitro bases for our hypothesis. Memantine blocked the extrasynaptic NMDA receptor 100 times more potently than the synaptic NMDA receptor at negative membrane potentials and the block of both types of NMDA receptors was attenuated with depolarization. However, galantamine potentiation of the NMDA receptors was not voltage dependent. Thus, co-application of memantine with galantamine prevented the galantamine potentiation and the activation of extrasynaptic NMDA receptors, but membrane depolarization revealed the galantamine potentiation. Therefore, cell death is expected to be prevented by memantine near the resting potential while the NMDA-mediated synaptic transmission, which is down-regulated in the patients, is maintained and potentiated by galantamine. These results provide in vitro bases for the beneficial actions of galantamine and memantine combinations.
"Moreover, the concomitant use of memantine plus donepezil is most efficient to reduce agitation than donepezil alone (Kano et al., 2013). Interestingly, galantamine, an ACh-esterase inhibitor used for AD treatment, not only potentiated nicotinic ACh receptors activity, but also improved NMDARs activity (Zhao et al., 2006); thus, concomitant use of memantine and galantamine prevented galantamine activation of extrasynaptic NMDARs (Zhao et al., 2006). A recent study has also demonstrated that memantine protects not only glutamatergic but also cholinergic septal neurons from Ab-induced toxicity (Colom et al., 2013) which may explain, in part, the potentiation of the effect of ACh-esterase inhibitor by memantine, when used concomitantly in AD treatment. "
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly. Alterations capable of causing brain circuitry dysfunctions in AD may take several years to develop. Oligomeric amyloid-beta peptide (Aβ) plays a complex role in the molecular events that lead to progressive loss of function and eventually to neurodegeneration in this devastating disease. Moreover, N-methyl-D-aspartate (NMDA) receptors (NMDARs) activation has been recently implicated in AD-related synaptic dysfunction. Thus, in this review we focus on glutamatergic neurotransmission impairment and the changes in NMDAR regulation in AD, following the description on the role and location of NMDARs at pre- and post-synaptic sites under physiological conditions. In addition, considering that there is currently no effective ways to cure AD or stop its progression, we further discuss the relevance of NMDARs antagonists to prevent AD symptomatology. This review posits additional information on the role played by Aβ in AD and the importance of targeting the tripartite glutamatergic synapse in early asymptomatic and possible reversible stages of the disease through preventive and/or disease-modifying therapeutic strategies.
"It is noteworthy that galantamine has been shown to selectively potentiate NMDA receptor activity (Moriguchi et al. 2004). Conversely, in a combined treatment with the two drugs, memantine was able to block tonic NMDA currents and Ca2+ influx promoted by galantamine, seemingly acting on the extrasynaptic NMDA channels, while synaptic NMDA currents were spared (Zhao et al. 2006). Therefore, the combined treatment should prevent the extrasynaptic NMDA overexcitation while promoting synaptic glutamatergic signaling in patients. "
[Show abstract][Hide abstract] ABSTRACT: The combination of memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist, with an acetylcholinesterase inhibitor (AChEI) is the current standard of care in Alzheimer's disease (AD). Galantamine, an AChEI currently marketed for the treatment of AD, exerts memory-enhancing and neuroprotective effects via activation of nicotinic acetylcholine receptors (nAChRs). Here, we investigated the neuroprotective properties of galantamine in primary cultures of rat cortical neurons when given alone or in combination with memantine. In agreement with previous findings, we found that memantine was fully effective in reversing NMDA toxicity at concentrations of 2.5 and 5 μmol/L. Galantamine also completely reversed NMDA toxicity at a concentration of 5 μmol/L. The α7 and α4β2 nAChR antagonists, methyllycaconitine, and dihydro-β-erythroidine blocked the neuroprotective effect of galantamine, demonstrating the involvement of nAChRs. The combination of memantine with galantamine produced synergistic actions, such that full neuroprotective efficacy, was obtained at inactive concentrations of memantine (0.1 μmol/L) and galantamine (1 μmol/L). A similar potentiation was also observed when memantine was replaced with ifenprodil, suggesting a possible involvement of the NR2B subunit of the NMDA receptor. In summary, our study reports for the first time at a cellular level that memantine and galantamine interact on the same excitotoxic cascade and that the combination of these two drugs can result in a remarkable neuroprotective effect.
Brain and Behavior 03/2013; 3(2):67-74. DOI:10.1002/brb3.118 · 2.24 Impact Factor
"An alternative approach to enhance α7 nAChR function is by augmenting effects of acetylcholine via positive allosteric modulation (PAM) that can reinforce the endogenous cholinergic tone without directly activating α7 nAChRs (see Maelicke, 2000). Various molecules have been reported to positively modulate α7 nAChRs, including PNU-120596 (Hurst et al., 2005), ivermectin (Krause et al., 1998) and galantamine (Zhao et al., 2006). PNU- 120596 represents a novel positive allosteric modulator at the α7 nAChRs, which can increase the maximal agonist-evoked current and slow the decay of the currents in the continued presence of an agonist. "
[Show abstract][Hide abstract] ABSTRACT: The α7 nicotinic acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia. Adult female hooded Lister rats received sub-chronic phencyclidine (PCP) (2 mg/kg) or vehicle i.p. twice daily for 7 days, followed by 7 days' washout. PCP-treated rats then received PNU-120596 (10 mg/kg; s.c.) or saline and were tested in the attentional set-shifting task. Sub-chronic PCP produced a significant cognitive deficit in the extra-dimensional shift (EDS) phase of the task (p < 0.001, compared with vehicle). PNU-120596 significantly improved performance of PCP-treated rats in the EDS phase of the attentional set-shifting task (p < 0.001). In conclusion, these data demonstrate that PNU-120596 improves cognitive dysfunction in our animal model of cognitive dysfunction in schizophrenia, most likely via modulation of α7 nACh receptors.
Journal of Psychopharmacology 12/2011; 26(9):1265-70. DOI:10.1177/0269881111431747 · 3.59 Impact Factor
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