CNS Drug Rev. 2003 Fall;9(3):275-308. Related Articles, Links
The neuropharmacological basis for the use of memantine in the treatment of Alzheimer's disease.
Rogawski MA, Wenk GL.
Epilepsy Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-4457, USA. michael.rogawski@nih.gov
Memantine has been demonstrated to be safe and effective in the symptomatic treatment of Alzheimer's disease (AD). While the neurobiological basis for the therapeutic activity of memantine is not fully understood, the drug is not a cholinesterase inhibitor and, therefore, acts differently from current AD therapies. Memantine can interact with a variety of ligand-gated ion channels. However, NMDA receptors appear to be a key target of memantine at therapeutic concentrations. Memantine is an uncompetitive (channel blocking) NMDA receptor antagonist. Like other NMDA receptor antagonists, memantine at high concentrations can inhibit mechanisms of synaptic plasticity that are believed to underlie learning and memory. However, at lower, clinically relevant concentrations memantine can under some circumstances promote synaptic plasticity and preserve or enhance memory in animal models of AD. In addition, memantine can protect against the excitotoxic destruction of cholinergic neurons. Blockade of NMDA receptors by memantine could theoretically confer disease-modifying activity in AD by inhibiting the "weak" NMDA receptor-dependent excitotoxicity that has been hypothesized to play a role in the progressive neuronal loss that underlies the evolving dementia. Moreover, recent in vitro studies suggest that memantine abrogates beta-amyloid (Abeta) toxicity and possibly inhibits Abeta production. Considerable attention has focused on the investigation of theories to explain the better tolerability of memantine over other NMDA receptor antagonists, particularly those that act by a similar channel blocking mechanism such as dissociative anesthetic-like agents (phencyclidine, ketamine, MK-801). A variety of channel-level factors could be relevant, including fast channel-blocking kinetics and strong voltage-dependence (allowing rapid relief of block during synaptic activity), as well as reduced trapping (permitting egress from closed channels). These factors may allow memantine to block channel activity induced by low, tonic levels of glutamate--an action that might contribute to symptomatic improvement and could theoretically protect against weak excitotoxicity--while sparing synaptic responses required for normal behavioral functioning, cognition and memory.
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Full Version: The neuropharmacological basis for the use of memantine in the treatment of Alzheimer's disease
"However, at lower, clinically relevant concentrations memantine can under some circumstances promote synaptic plasticity and preserve or enhance memory in animal models of AD"
Under what circumstances?
Under what circumstances?
[quote name='Unknown' date='Nov 11, 2004, 02:42 PM' post='42388']
CNS Drug Rev. 2003 Fall;9(3):275-308. Related Articles, Links
The neuropharmacological basis for the use of memantine in the treatment of Alzheimer's disease.
Rogawski MA, Wenk GL.
Epilepsy Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-4457, USA. michael.rogawski@nih.gov
Memantine has been demonstrated to be safe and effective in the symptomatic treatment of Alzheimer's disease (AD). While the neurobiological basis for the therapeutic activity of memantine is not fully understood, the drug is not a cholinesterase inhibitor and, therefore, acts differently from current AD therapies. Memantine can interact with a variety of ligand-gated ion channels. However, NMDA receptors appear to be a key target of memantine at therapeutic concentrations. Memantine is an uncompetitive (channel blocking) NMDA receptor antagonist. Like other NMDA receptor antagonists, memantine at high concentrations can inhibit mechanisms of synaptic plasticity that are believed to underlie learning and memory.
However, at lower, clinically relevant concentrations memantine can under some circumstances promote synaptic plasticity and preserve or enhance memory in animal models of AD. In addition, memantine can protect against the excitotoxic destruction of cholinergic neurons.
>>>Concentrations of a drug like memantine alone to promote synaptic plasticity is not very true. the drug simply acts as an uncompetitive antagonist for its affinity to NMDA receptors binding that will inhibit a longer ca2+ influx, but this doesn't mean that it'll promote a synaptic plasticity itself. the drug changes the affinity of the subunits within NMDA receptors that dec [ca2+] conc. but I think this study referring to states within plasticity caused by the drug in terms of current states influenced by neurochemicals like glutamate conc.
studies suggest that plasticity is only strengthened or weakened by the activity of specific neuronal input seen at synapse where high frequency EPSP signals generated due to bringing more AMPA receptors at synapse responsible for cases like (LTP) Long-Term Potentiation which is primarily input specific. and effect of memantine is not determined in cases of finding induced higher -frequency stimulation from a set baseline responses through activity of NMDA receptors alone. Studies also show that there are experience-dependent changes in selectivity of neurons that reflect synaptic regulation and could be arranged on multiple set of neurons. in this case it is hard to believe if this drug really works on those regulatory signals responsible for plasticity.
Blockade of NMDA receptors by memantine could theoretically confer disease-modifying activity in AD by inhibiting the "weak" NMDA receptor-dependent excitotoxicity that has been hypothesized to play a role in the progressive neuronal loss that underlies the evolving dementia.
>>>disease modifying activity? inhibit weak NMDA receptor dep- excitotoxicity....how can memantine and the dosage-dependency of NMDA receptors blockade alone provide enough evidence or suggests that weak NMDA recptor-dep. excitotoxicity are also involved in progressive neuronal loss.
Moreover, recent in vitro studies suggest that memantine abrogates beta-amyloid (Abeta) toxicity and possibly inhibits Abeta production. Considerable attention has focused on the investigation of theories to explain the better tolerability of memantine over other NMDA receptor antagonists, particularly those that act by a similar channel blocking mechanism such as dissociative anesthetic-like agents (phencyclidine, ketamine, MK-801). A variety of channel-level factors could be relevant, including fast channel-blocking kinetics and strong voltage-dependence (allowing rapid relief of block during synaptic activity), as well as reduced trapping (permitting egress from closed channels).
These factors may allow memantine to block channel activity induced by low, tonic levels of glutamate--an action that might contribute to symptomatic improvement and could theoretically protect against weak excitotoxicity--while sparing synaptic responses required for normal behavioral functioning, cognition and memory.
Like other NMDA receptor antagonists, memantine at high concentrations can inhibit mechanisms of synaptic plasticity that are believed to underlie learning and memory.
>>> you are able to block the NMDA ionotropic channels and decrease or lose its functional activity using those dosage-effect where neurotransmitters are responsible for mechanisms of synaptic plasticity,you will not inhibit plasticity at this level but only weaken it . plasticity would not only depend on inactivation of NMDA receptor to mediate the calcium influx, there are many factors to consider like input specific activation required from regions within the presynaptic neurons onto postsynaptic neurons conducting frequency higher than normal. agents like phencyclidine don't directly block NMDA receptor channels but rather inhibit depolarization of cations into neuronal cells that have different function -unrelated to ones involved in plasticity of learning and memory. therefore we can't fully set a good explanation of how those agents work to correlate those studies on memantine affecting memory and learning and in treating AD.
Have a look at:
Debanne, D.; Daoudal G., Sourdet V., and Russier M. (2003). "Brain plasticity and ion channels". Journal of Physiology, Paris 97 (4-6): 403-414.
Song, I.; Huganir R.L. (2002). "Regulation of AMPA receptors during synaptic plasticity". Trends in Neurosciences 25 (11): 578-589
Boron, Walter F.. Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. ISBN 1-4160-2328-3
CNS Drug Rev. 2003 Fall;9(3):275-308. Related Articles, Links
The neuropharmacological basis for the use of memantine in the treatment of Alzheimer's disease.
Rogawski MA, Wenk GL.
Epilepsy Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-4457, USA. michael.rogawski@nih.gov
Memantine has been demonstrated to be safe and effective in the symptomatic treatment of Alzheimer's disease (AD). While the neurobiological basis for the therapeutic activity of memantine is not fully understood, the drug is not a cholinesterase inhibitor and, therefore, acts differently from current AD therapies. Memantine can interact with a variety of ligand-gated ion channels. However, NMDA receptors appear to be a key target of memantine at therapeutic concentrations. Memantine is an uncompetitive (channel blocking) NMDA receptor antagonist. Like other NMDA receptor antagonists, memantine at high concentrations can inhibit mechanisms of synaptic plasticity that are believed to underlie learning and memory.
However, at lower, clinically relevant concentrations memantine can under some circumstances promote synaptic plasticity and preserve or enhance memory in animal models of AD. In addition, memantine can protect against the excitotoxic destruction of cholinergic neurons.
>>>Concentrations of a drug like memantine alone to promote synaptic plasticity is not very true. the drug simply acts as an uncompetitive antagonist for its affinity to NMDA receptors binding that will inhibit a longer ca2+ influx, but this doesn't mean that it'll promote a synaptic plasticity itself. the drug changes the affinity of the subunits within NMDA receptors that dec [ca2+] conc. but I think this study referring to states within plasticity caused by the drug in terms of current states influenced by neurochemicals like glutamate conc.
studies suggest that plasticity is only strengthened or weakened by the activity of specific neuronal input seen at synapse where high frequency EPSP signals generated due to bringing more AMPA receptors at synapse responsible for cases like (LTP) Long-Term Potentiation which is primarily input specific. and effect of memantine is not determined in cases of finding induced higher -frequency stimulation from a set baseline responses through activity of NMDA receptors alone. Studies also show that there are experience-dependent changes in selectivity of neurons that reflect synaptic regulation and could be arranged on multiple set of neurons. in this case it is hard to believe if this drug really works on those regulatory signals responsible for plasticity.
Blockade of NMDA receptors by memantine could theoretically confer disease-modifying activity in AD by inhibiting the "weak" NMDA receptor-dependent excitotoxicity that has been hypothesized to play a role in the progressive neuronal loss that underlies the evolving dementia.
>>>disease modifying activity? inhibit weak NMDA receptor dep- excitotoxicity....how can memantine and the dosage-dependency of NMDA receptors blockade alone provide enough evidence or suggests that weak NMDA recptor-dep. excitotoxicity are also involved in progressive neuronal loss.
Moreover, recent in vitro studies suggest that memantine abrogates beta-amyloid (Abeta) toxicity and possibly inhibits Abeta production. Considerable attention has focused on the investigation of theories to explain the better tolerability of memantine over other NMDA receptor antagonists, particularly those that act by a similar channel blocking mechanism such as dissociative anesthetic-like agents (phencyclidine, ketamine, MK-801). A variety of channel-level factors could be relevant, including fast channel-blocking kinetics and strong voltage-dependence (allowing rapid relief of block during synaptic activity), as well as reduced trapping (permitting egress from closed channels).
These factors may allow memantine to block channel activity induced by low, tonic levels of glutamate--an action that might contribute to symptomatic improvement and could theoretically protect against weak excitotoxicity--while sparing synaptic responses required for normal behavioral functioning, cognition and memory.
Like other NMDA receptor antagonists, memantine at high concentrations can inhibit mechanisms of synaptic plasticity that are believed to underlie learning and memory.
>>> you are able to block the NMDA ionotropic channels and decrease or lose its functional activity using those dosage-effect where neurotransmitters are responsible for mechanisms of synaptic plasticity,you will not inhibit plasticity at this level but only weaken it . plasticity would not only depend on inactivation of NMDA receptor to mediate the calcium influx, there are many factors to consider like input specific activation required from regions within the presynaptic neurons onto postsynaptic neurons conducting frequency higher than normal. agents like phencyclidine don't directly block NMDA receptor channels but rather inhibit depolarization of cations into neuronal cells that have different function -unrelated to ones involved in plasticity of learning and memory. therefore we can't fully set a good explanation of how those agents work to correlate those studies on memantine affecting memory and learning and in treating AD.
Have a look at:
Debanne, D.; Daoudal G., Sourdet V., and Russier M. (2003). "Brain plasticity and ion channels". Journal of Physiology, Paris 97 (4-6): 403-414.
Song, I.; Huganir R.L. (2002). "Regulation of AMPA receptors during synaptic plasticity". Trends in Neurosciences 25 (11): 578-589
Boron, Walter F.. Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. ISBN 1-4160-2328-3
QUOTE(dutch84 @ Nov 30, 2007, 04:57 AM) 
"However, at lower, clinically relevant concentrations memantine can under some circumstances promote synaptic plasticity and preserve or enhance memory in animal models of AD"
Under what circumstances?
Under no circumstances. drugs will never function in manner similar to neuronal activity. it depends on the genetic characteristics within a nueron that allows it to be plastic!
Have a look at
Debanne, D.; Daoudal G., Sourdet V., and Russier M. (2003). "Brain plasticity and ion channels". Journal of Physiology, Paris 97 (4-6): 403-414.
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