Failures and successes of NMDA receptor antagonists: molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults

Abstract

Excitotoxicity, defined as excessive exposure to the neurotransmitter glutamate or overstimulation of its membrane receptors, has been implicated as one of the key factors contributing to neuronal injury and death in a wide range of both acute and chronic neurologic disorders. Excitotoxic cell death is due, at least in part, to excessive activation of N-methyl-D-aspartate (NMDA)-type glutamate receptors and hence excessive Ca2+ influx through the receptor's associated ion channel. Physiological NMDA receptor activity, however, is also essential for normal neuronal function; potential neuroprotective agents that block virtually all NMDA receptor activity will very likely have unacceptable clinical side effects. For this reason many NMDA receptor antagonists have disappointingly failed advanced clinical trials for a number of diseases including stroke and neurodegenerative disorders such as Huntington's disease. In contrast, studies in my laboratory were the first to show that memantine, an adamantane derivative, preferentially blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this through its action as an open-channel blocker; it enters the receptor-associated ion channel preferentially when it is excessively open, and, most importantly, its off-rate is relatively fast so that it does not substantially accumulate in the channel to interfere with normal synaptic transmission. Past clinical use for other indications has demonstrated that memantine is well tolerated, and it has recently been approved in both Europe and the USA for the treatment of dementia of the Alzheimer's type. Clinical studies of the safety and efficacy of memantine for other neurological disorders, including glaucoma and other forms of dementia, are currently underway. A series of second-generation memantine derivatives are currently in development and may prove to have even greater neuroprotective properties than does memantine. These second-generation drugs take advantage of the fact that the NMDA receptor has other modulatory sites, in addition to its ion channel, that could potentially be used for safe but effective clinical intervention.

FIG. 1.

Schematic illustration of some apoptotic pathways triggered by excessive NMDA receptor activity. The cascade of steps leading to neuronal cell death include: 1) NMDA receptor (NMDA-Rc) hyperactivation, 2) activation of the p38 MAPK-MEF2C (transcription factor) pathway (MEF2 is subsequently cleaved by caspases to form an endogenous dominant-interfering form that contributes to neuronal cell death), 3) toxic effects of free radicals such as NO and reactive oxygen species (ROS), and 4) activation of apoptosis-inducing enzymes including caspases. cyt c, cytochrome c. (Adapted from the Lipton website at http://www.burnham.org).

FIG. 2.

NMDA receptor model illustrating important binding and modulatory sites. Glu or NMDA, glutamate or NMDA binding site; Gly, glycine binding site; Zn²⁺, zinc binding site; NR1, NMDA receptor subunit 1; NR2, NMDA receptor subunit 2A; SNO, cysteine sulfhydryl group (−SH) reacting with NO species; X, Mg²⁺, MK-801, and memantine binding sites within the ion channel pore region.

FIG. 3.

Chemical structure of memantine. Several important features are 1) the three-ring structure, 2) the bridgehead amine (−NH₂ group), which is charged at the physiological pH of the body (−NH₃⁺) and represents the region of memantine that binds at or near the Mg²⁺ binding site in the NMDA receptor-associated ion channel, and 3) the methyl group (−CH₃) side-chains (unlike amantadine), which serve to stabilize the interaction of memantine in the channel region of the NMDA receptor.

FIG. 4.

Blockade of NMDA current by memantine. At a holding potential of approximately −50 mV, whole-cell recording of NMDA-evoked current from a solitary neuron revealed that the on-time (time until peak blockade) of micromolar memantine was approximately 1 second, while the off-time (recovery time) from the effect was ∼5.5 seconds. The application of memantine produced an effective blockade only during NMDA receptor activation, consistent with the notion that its mechanism of action is open-channel block.

FIG. 5.

Paradoxically, a fixed dose of memantine (e.g., 1 μm) blocks the effect of increasing concentrations of NMDA to a greater degree than lower concentrations of NMDA. This finding is characteristic of an uncompetitive antagonist.