Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity

Abstract

Excessive activation of NMDA receptors is thought to mediate the calcium-dependent neurotoxicity associated with hypoxic-ischemic brain injury, trauma, epilepsy, and several neurodegenerative diseases. For this reason, various NMDA antagonists have been investigated for their therapeutic potential in these diseases, but heretofore none have proven to be both effective and safe. In the present study, memantine, an adamantane derivative similar to the antiviral drug amantadine, is shown to block the channels activated by NMDA receptor stimulation. From whole-cell and single-channel recording experiments, the mechanism of action of memantine is deduced to be open-channel block, similar to MK-801; however, unlike MK-801, memantine is well tolerated clinically. Compared to MK-801, memantine's safety may be related to its faster kinetics of action with rapid blocking and unblocking rates at low micromolar concentrations. Furthermore, at these levels memantine is an uncompetitive antagonist and should theoretically allow near-normal physiological NMDA activity throughout the brain even in the face of pathologically high focal concentrations of glutamate. These pharmacological properties confer upon memantine a therapeutic advantage against NMDA receptor-mediated neurotoxicity with few side effects compared with other organic NMDA open-channel blockers. Moreover, memantine is increasingly effective against escalating levels of glutamate, such as those observed during a stroke. Low micromolar concentrations of memantine, levels known to be tolerated by patients receiving the drug for the treatment of Parkinson's disease, prevent NMDA receptor-mediated neurotoxicity in cultures of rat cortical and retinal ganglion cell neurons; memantine also appears to be both safe and effective in a rat stroke model. These results suggest that memantine has considerable therapeutic potential for the myriad of clinical entities associated with NMDA receptor-mediated neurotoxicity.

Effects of Memantine on Neuronal Structure and Conditioned Fear in the Tg2576 Mouse Model of Alzheimer's Disease

“…Memantine, an uncompetitive antagonist at NMDA receptors (Kornhuber et al, 1989;Chen et al, 1992), is now widely prescribed for the treatment of moderate-to-severe Alzheimer's disease (AD). Memantine is rapidly displaced from the NMDA receptor, which may avoid prolonged receptor blockade and the detrimental effects on learning and memory associated with prolonged blockade of the NMDA receptor (Lipton, 2006).…”

“…The rationale for using memantine in AD patients is based on the hypothesis that blockade of NMDA receptormediated excitotoxicity can help preserve neuronal structure and function (Lipton, 2006(Lipton, , 2007Wenk et al, 2006). The ability of memantine to protect neurons against NMDA-or glutamate-induced excitotoxicity has been shown in vitro (Erdö and Schäfer, 1991;Chen et al, 1992;Weller et al, 1993), and in animal models of neurodegenerative disease (Wenk et al, 1995(Wenk et al, , 1997(Wenk et al, , 2006MiguelHidalgo et al, 2002). Therefore, it has been proposed that memantine can improve cognition in AD and perhaps even slow disease progression by blocking NMDA receptormediated excitotoxicity (Ditzler, 1991;Frankiewicz et al, 2000;Reisberg et al, 2003;Lipton, 2006).…”

Memantine for prevention of migraine: a retrospective study of 60 cases

“…NMDA receptor antagonists are known to inhibit cortical spreading depression (CSD), which is believed to be a fundamental mechanism of migraine. Memantine is a low-affinity, open channel blocker of NMDA receptor channels that is FDA approved in the United States for the treatment of Alzheimer's disease [2,3]. We have used memantine to treat patients with headache, the majority of whom had failed standard acute and preventive therapy.…”

Effects of memantine and MK‐801 on NMDA‐induced currents in cultured neurones and on synaptic transmission and LTP in area CA1 of rat hippocampal slices

“…Memantine (1-amino-3,5-dimethyladmantane) is an uncompetitive NMDA (N-methyl-D-aspartate) receptor antagonist (Kornhuber et al, 1989;1991;Bormann, 1989;Chen et al, 1992;Parsons et al, 1993;1995a, b) that has been used clinically for many years in the treatment of spasticity and to a lesser exent Parkinson's disease (Grossmann & Schutz, 1982;Wesemann et al, 1983;Schneider et al, 1984;Kornhuber et al, 1994;Danysz et al, 1994a;. More recently, doses of this compound predicted to act selectively at NMDA receptors in vivo have been found to produce symptomatological improvements in the therapy of dementia (Ditzler, 1991;G6rtelmeyer & Erbler, 1992;Pantev et al, 1993).…”

“…This promising profile of memantine has been attributed to its strong voltage-dependency and rapid, open-channel unblocking kinetics which may allow it to block the patho-logical activation of NMDA receptors whilst leaving their physiological activation relatively intact (Chen et al, 1992;Parsons et al, 1993;1995b). The aim of the present study was to test whether these biophysical properties of memantine do indeed lessen its effects on the physiological activation of NMDA receptors, by assessing the potency of memantine and MK-801 (dizocilpine, (+ )-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate) in blocking the induction of LTP in area CAI of hippocampal slices and comparing these effects to the kinetics and voltagedependency of NMDA receptor blockade in cultured neurones.…”