Efficacy and Safety of Memantine, an NMDA-Type Open-Channel Blocker, for Reduction of Retinal Injury Associated with Experimental Glaucoma in Rat and Monkey

Hare, William A.; WoldeMussie, Elizabeth; Lai, Ronald; Ton, Hau; Ruíz, Guadalupe; Feldmann, Barbara; Wijono, Mercy; Chun, Teresa; Wheeler, Larry A.

doi:10.1016/s0039-6257(01)00200-4

Cited by 107 publications

(51 citation statements)

References 9 publications

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“…Elevation of endogenous glutamate and activation of glutamate receptors contribute to a variety of acute and chronic neurological disorders, including hypoxicischemic brain injury (stroke), trauma, seizures, and various forms of dementia and neurodegeneration (Kalia et al, 2008). In the retina, excess glutamate has been proposed to underlie common neurodegenerative disorders, including glaucoma and retinal artery occlusion (Hare et al, 2001(Hare et al, , 2004Casson, 2006;Seki and Lipton, 2008). The central hypothesis for excitotoxic injury is that excess glutamate binds to cell surface NMDA receptors on neurons, triggers massive Ca 2ϩ influx, and activates proapoptotic signaling cascades.…”

Section: Introductionmentioning

confidence: 99%

Excitotoxic Death of Retinal NeuronsIn VivoOccurs via a Non-Cell-Autonomous Mechanism

Lebrun-Julien

Duplan²,

Pernet³

et al. 2009

J. Neurosci.

167

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The central hypothesis of excitotoxicity is that excessive stimulation of neuronal NMDA-sensitive glutamate receptors is harmful to neurons and contributes to a variety of neurological disorders. Glial cells have been proposed to participate in excitotoxic neuronal loss, but their precise role is defined poorly. In this in vivo study, we show that NMDA induces profound nuclear factor B (NF-B) activation in Müller glia but not in retinal neurons. Intriguingly, NMDA-induced death of retinal neurons is effectively blocked by inhibitors of NF-B activity. We demonstrate that tumor necrosis factor ␣ (TNF␣) protein produced in Müller glial cells via an NMDA-induced NF-B-dependent pathway plays a crucial role in excitotoxic loss of retinal neurons. This cell loss occurs mainly through a TNF␣-dependent increase in Ca 2ϩ -permeable AMPA receptors on susceptible neurons. Thus, our data reveal a novel non-cell-autonomous mechanism by which glial cells can profoundly exacerbate neuronal death following excitotoxic injury.

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Section: Introductionmentioning

confidence: 99%

Excitotoxic Death of Retinal NeuronsIn VivoOccurs via a Non-Cell-Autonomous Mechanism

Lebrun-Julien

Duplan²,

Pernet³

et al. 2009

J. Neurosci.

167

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“…Uncompetitive antagonists are also proposed to have therapeutic advantages, because their degree of antagonism increases as the level of agonist increases (Ascher et al, 1978;Chen et al, 1992). Accordingly, uncompetitive NMDA open channel blockers, such as memantine, have been thoroughly researched over the past decade (Chen and Lipton, 1997;Kemp and McKernan, 2002) and have been shown to be relatively safe and effective 'neuroprotective agents' in animal models (Stieg et al, 1999;Hare et al, 2001). Another direction for NMDA blocker development is the assessment of subtype-selective antagonists like the NR2B-selective antagonist, ifenprodil and its analogs (Kew et al, 1996(Kew et al, , 1998.…”

Section: Introductionmentioning

confidence: 99%

Underlying mechanism for NMDA receptor antagonism by the anti-inflammatory drug, sulfasalazine, in mouse cortical neurons

2006

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“…An uncompetitive antagonist is defined as a drug whose inhibitory effect is contingent upon prior activation of the channel by agonist, and a fixed concentration of antagonist blocks the response to high concentrations of ago-* This work was supported by grants from the Research Grants Council of nist to a greater extent than the response to low concentrations of agonist (11). A clear advantage of compounds of this type is that they preferentially blocked overactivated (in a tonic rather than phasic manner) channels while sparing physiological neurotransmission mediated by NMDA receptors (12)(13)(14). However, for uncompetitive antagonists, the off-rate and affinity further determine the clinical tolerability.…”

Section: N-methyl-d-aspartate (Nmda)mentioning

confidence: 99%

Pathologically Activated Neuroprotection via Uncompetitive Blockade of N-Methyl-d-aspartate Receptors with Fast Off-rate by Novel Multifunctional Dimer Bis(propyl)-cognitin

Luo

Zhao³

et al. 2010

Journal of Biological Chemistry

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Uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists with fast off-rate (UFO) may represent promising drug candidates for various neurodegenerative disorders. In this study, we report that bis(propyl)-cognitin, a novel dimeric acetylcholinesterase inhibitor and ␥-aminobutyric acid subtype A receptor antagonist, is such an antagonist of NMDA receptors. In cultured rat hippocampal neurons, we demonstrated that bis-(propyl)-cognitin voltage-dependently, selectively, and moderately inhibited NMDA-activated currents. The inhibitory effects of bis(propyl)-cognitin increased with the rise in NMDA and glycine concentrations. Kinetics analysis showed that the inhibition was of fast onset and offset with an off-rate time constant of 1.9 s. Molecular docking simulations showed moderate hydrophobic interaction between bis(propyl)-cognitin and the MK-801 binding region in the ion channel pore of the NMDA receptor. Bis(propyl)-cognitin was further found to compete with [ 3 H]MK-801 with a K i value of 0.27 M, and the mutation of NR1(N616R) significantly reduced its inhibitory potency. Under glutamate-mediated pathological conditions, bis(propyl)-cognitin, in contrast to bis(heptyl)-cognitin, prevented excitotoxicity with increasing effectiveness against escalating levels of glutamate and much more effectively protected against middle cerebral artery occlusion-induced brain damage than did memantine. More interestingly, under NMDA receptor-mediated physiological conditions, bis(propyl)-cognitin enhanced longterm potentiation in hippocampal slices, whereas MK-801 reduced and memantine did not alter this process. These results suggest that bis(propyl)-cognitin is a UFO antagonist of NMDA receptors with moderate affinity, which may provide a pathologically activated therapy for various neurodegenerative disorders associated with NMDA receptor dysregulation.Neurodegenerative disorders are among the leading cause of death in the elderly, and this medical problem is expected to become more serious as the population continues to age. N-Methyl-D-aspartate (NMDA)3 receptor overactivation-induced excitotoxicity is clearly implicated in a variety of acute and chronic neurodegenerative disorders (1-4). Thus, the NMDA receptor has been considered an attractive therapeutic target for the development of neuroprotectants. However, the NMDA receptor, as the major excitatory neurotransmitter receptor in the central nervous system, mediates many important physiological processes, such as excitatory neurotransmission, synaptic plasticity, learning and memory, and cell survival (5-8). The therapeutic potential of many NMDA receptor antagonists, therefore, was limited, and they failed in clinical trials because of their psychotropic side effects and memoryimpairing effects resulting from the blockade of NMDA receptor-mediated physiological activities (9, 10). Clinically well tolerated and effective NMDA receptor antagonists for the therapy of neurodegenerative disorders have been pursued over the past several decades.The strategies applie...

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Efficacy and Safety of Memantine, an NMDA-Type Open-Channel Blocker, for Reduction of Retinal Injury Associated with Experimental Glaucoma in Rat and Monkey

Cited by 107 publications

References 9 publications

Excitotoxic Death of Retinal NeuronsIn VivoOccurs via a Non-Cell-Autonomous Mechanism

Excitotoxic Death of Retinal NeuronsIn VivoOccurs via a Non-Cell-Autonomous Mechanism

Underlying mechanism for NMDA receptor antagonism by the anti-inflammatory drug, sulfasalazine, in mouse cortical neurons

Pathologically Activated Neuroprotection via Uncompetitive Blockade of N-Methyl-d-aspartate Receptors with Fast Off-rate by Novel Multifunctional Dimer Bis(propyl)-cognitin

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