Pathologically-Activated Therapeutics for Neuroprotection: Mechanism of NMDA Receptor Block by Memantine and S-Nitrosylation

The Burnham Institute for Medical Research, The Salk Institute for Biological Studies, The Scripps Research Institute, and the University of California--San Diego, La Jolla, California 92037, USA.
Current drug targets (Impact Factor: 3.02). 06/2007; 8(5):621-32. DOI: 10.2174/138945007780618472
Source: PubMed


Alzheimer's disease (AD) and Vascular dementia represent the most common forms of dementia. If left unabated, the economic cost of caring for patients with these maladies would consume the entire gross national product of the industrialized world by the middle of this century. Until recently, the only available drugs for this condition were cholinergic treatments, which symptomatically enhance cognitive state to some degree, but they were not neuroprotective. Many potential neuroprotective drugs tested in clinical trials failed because of intolerable side effects. However, after our discovery of its clinically-tolerated mechanism of action, one putatively neuroprotective drug, memantine, was recently approved by the European Union and the U.S. Food and Drug Administration (FDA) for the treatment of dementia. Recent phase 3 clinical trials have shown that memantine is effective in the treatment of both mild and moderate-to-severe Alzheimer's disease and possibly Vascular dementia (multi-infarct dementia). Here we review the molecular mechanism of memantine's action and also the basis for the drug's use in these neurological diseases, which are mediated at least in part by excitotoxicity. Excitotoxicity is defined as excessive exposure to the neurotransmitter glutamate or overstimulation of its membrane receptors, leading to neuronal injury or death. Excitotoxic neuronal cell damage is mediated in part by overactivation of N-methyl-D-aspartate (NMDA)-type glutamate receptors, which results in excessive Ca(2+) influx through the receptor associated ion channel and subsequent free radical formation. Physiological NMDA receptor activity, however, is also essential for normal neuronal function. This means that potential neuroprotective agents that block virtually all NMDA receptor activity will very likely have unacceptable clinical side effects. For this reason many previous NMDA receptor antagonists have disappointingly failed advanced clinical trials for a number of neurodegenerative disorders. In contrast, studies in our laboratory have shown that the adamantane derivative, memantine, preferentially blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this through its action as an uncompetitive, low-affinity, 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 subsequent normal synaptic transmission. Clinical use has corroborated the prediction that memantine is well tolerated. Besides Alzheimer's disease, memantine is currently in trials for additional neurological disorders, including HIV-associated dementia, depression, glaucoma, and severe neuropathic pain. A series of second-generation memantine derivatives are currently in development and may prove to have even greater neuroprotective properties than 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 potentially could also be used for safe but effective clinical intervention.

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    • "S - nitrosylation has also been implicated in AD ( Lipton et al . , 1993 ) , exhibiting a modulatory effect on glutamatergic NMDA receptors ( Lipton , 2007b ) . Over - stimulation of NMDA receptors may produce an excessive Ca 2+ influx that can generate ROS and activate excitotoxicity processes that lead to cell death . "
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    ABSTRACT: Nitric oxide (NO) is a pleiotropic janus-faced molecule synthesized by nitric oxide synthases (NOS) which plays a critical role in a number of physiological and pathological processes in humans. The physiological roles of NO depend on its local concentrations, as well as its availability and the nature of downstream target molecules. Its double-edged sword action has been linked to neurodegenerative disorders. Excessive NO production, as the evoked by inflammatory signals, has been identified as one of the major causative reasons for the pathogenesis of several neurodegenerative diseases. Moreover, excessive NO synthesis under neuroinflammation leads to the formation of reactive nitrogen species and neuronal cell death. There is an intimate relation between microglial activation, NO and neuroinflammation in the human brain. The role of NO in neuroinflammation has been defined in animal models where this neurotransmitter can modulate the inflammatory process acting on key regulatory pathways, such as those associated with excitotoxicity processes induced by glutamate accumulation and microglial activation. Activated glia express inducible NOS and produce NO that triggers calcium mobilization from the endoplasmic reticulum, activating the release of vesicular glutamate from astroglial cells resulting in neuronal death. This change in microglia potentially contributes to the increased age-associated susceptibility and neurodegeneration. In the current review, information is provided about the role of NO, glial activation and age-related processes in the central nervous system (CNS) that may be helpful in the isolation of new therapeutic targets for aging and neurodegenerative diseases.
    Full-text · Article · Aug 2015 · Frontiers in Cellular Neuroscience
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    • "Then, given the role of NMDA receptors in Aβ-induced synaptic dysfunction, we directly tested the hypothesis that a NMDA receptor-blocking dose of memantine (5 mg/kg i.p.), clinically used to treat AD, could counteract the consolidation/retrieval failure observed in sAβ-treated rats. Memantine is an NMDA receptor open channel blocker, which has been found to act with a low-to-moderate affinity at therapeutic concentrations (Lipton, 2007; Parsons and Gilling, 2007; Parsons et al., 2007). Unlike many high affinity antagonists (Ikonomidou and Turski, 2002), it preferentially blocks excessive or inappropriate activation of NMDA receptors, while leaving physiological NMDA receptor-mediated activity unaffected (Lipton, 2007; Parsons and Gilling, 2007; Parsons et al., 2007). "
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    ABSTRACT: It has been well documented that β-amyloid peptide accumulation and aggregation in the brain plays a crucial role in the pathophysiology of Alzheimer’s disease (AD). However, a new orientation of the amyloid cascade hypothesis has evidenced that soluble forms of the peptide (sAβ) are involved in Aβ-induced cognitive impairment and cause rapid disruption of the synaptic mechanisms underlying memory. The primary aim of this study was to elucidate the effects of sAβ, acutely injected intracerebrally (i.c.v., 4 µM), on the short term and long term memory of young adult male rats, by using the novel object recognition task. Glutamatergic receptors have been proposed as mediating the effect of Aβ on synaptic plasticity and memory. Thus, we also investigated the effects of sAβ on prefrontal cortex (PFC) glutamate release and the specific contribution of N-methyl-D-aspartate (NMDA) receptor modulation to the effects of sAβ administration on the cognitive parameters evaluated. We found that a single i.c.v. injection of sAβ 2h before testing did not alter the ability of rats to differentiate between a familiar and a novel object, in a short term memory test, while it was able to negatively affect consolidation/retrieval of long term memory. Moreover, a significant increase of glutamate levels was found in PFC of rats treated with the peptide 2 h earlier. Interestingly, memory deficit induced by sAβ was reversed by a NMDA-receptor antagonist, memantine (5 mg/kg i.p), administered immediately after the familiarization trial (T1). On the contrary, memantine administered 30 min before T1 trial, was not able to rescue long term memory impairment. Taken together, our results suggest that an acute i.c.v. injection of sAβ peptide interferes with the consolidation/retrieval of long term memory. Moreover, such sAβ-induced effect indicates the involvement of glutamatergic system, proposing that NMDA receptor inhibition might prevent or lead to the recovery of early cognitive impairment.
    Full-text · Article · Sep 2014 · Frontiers in Behavioral Neuroscience
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    • "This, in turn, leads to loss of NMDAR density and loss of NMDAR expressing cells [27] in these regions, followed by secondary neuroinflammation in response to neuronal loss and disease progression. This model is supported by the correlation between regional neuroinflammation, but not plaque load, and cognitive abilities [7,21]; the decreased risk of AD in users of non steroidal anti-inflammatory agents coupled with the lack of efficacy of the same drugs in symptomatic AD [28,29], evidence of neuroinflammation in subjects with mild cognitive impairment who later converted to dementia [30] and the efficacy of memantine, a low-affinity non-competitive NMDAR antagonist which protects physiological synaptic transmission through NMDAR, in moderate to severe AD [31]. Furthermore, the close association between the region-specific decrease in NMDAR density and the progression of definite AD supports the use of positron-emitting NMDAR antagonists such as [11C]CNS5161 [32,33] in the diagnosis and staging of AD in vivo. "
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    ABSTRACT: Early Alzheimer's disease (AD) is characterized by memory loss and hippocampal atrophy with relative sparing of basal ganglia. Activation of glutamate NMDA receptors in the hippocampus is an important step in memory formation. We measured the density of NMDA receptors in samples of hippocampus, entorhinal cortex and basal ganglia obtained from subjects who died with pathologically confirmed AD and age- and sex- matched non-demented controls. We found significant decreases in NMDA receptor density in the hippocampus and entorhinal cortex but not in the basal ganglia. Loss of NMDA receptors was significantly correlated with neuropathological progression as assessed by Braak staging postmortem. The same samples were probed for neuroinflammation by measuring the density and gene expression of translocator protein 18kDA (TSPO), an established marker of microglial activation. Unlike NMDA receptor loss, increased densities of TSPO were found in all of the brain regions sampled. However hippocampal, but not striatal TSPO density and gene expression were inversely correlated with NMDA receptor density and positively correlated with Braak stage, suggesting NMDA receptors exacerbate neuroniflammatory damage. The high correlation between hippocampal NMDA receptor loss and disease progression supports the use of non invasive imaging with NMDA receptor tracers and positron emission tomography as a superior method for diagnosis, staging and treatment monitoring of AD in vivo.
    Full-text · Article · Nov 2013 · PLoS ONE
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