The role of glutamate in dementia
Glutamate is an excitatory neurotransmitter, but may also act as an endogenous neurotoxin. There is good evidence for an involvement of the glutamatergic system in the pathophysiology of dementia. The glutamatergic transmission machinery is quite complex
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Glutamate is an excitatory neurotransmitter, but may also act as an endogenous neurotoxin. There is good evidence for an involvement of the glutamatergic system in the pathophysiology of dementia. The glutamatergic transmission machinery is quite complex and provides a gallery of possible drug targets. There are good arguments both for an agonist and an antagonist strategy. When following the antagonist strategy, the goal is to provide neuroprotective effects via glutamate receptor antagonisms without inhibiting the physiological transmission that is required for learning and memory formation. When following the agonist strategy, the goal is to activate glutamatergic transmission without neurotoxic side effects. Several available anti dementia drugs may modulate the glutamatergic transmission. Summary.
The pathogenesis of the most frequent type of dementia, i.e. Alzheimer's disease, is poorly understood. Currently, there is an enormous need for an effective pharmacotherapy that either slows the rate of progression or produces clinically significant improvement in symptoms. This short overview describes the role of the excitatory neurotransmitter glutamate in Alzheimer's disease. Glutamate is the transmitter used, e.g., in corticocortical association neurons and in intrahippocampal fibers. Glutamatergic mechanisms are involved in fast synaptic transmission as well as in learning and memory processes. But, under certain conditions, glutamate may become a neurotoxin leading to slowly progressive as well as acute neuronal cell loss. These properties of the glutamatergic system led to the hypothesis that there might be a glutamatergic strategy for the treatment of Alzheimer's disease and also other dementia syndromes (Greenamyre et al., 1985; Greenamyre et al., 1988; Lawlor and Davis, 1992). Glutamate as a neurotransmitter
Glutamate is the principal excitatory neurotransmitters in the brain and probably acts at more than half of all its synapses. Glutamate receptor activity is required for various physiological neuronal processes including execution of motor acts, acquisition of memory, and perception (Bliss and Collingridge, 1993; Choi, 1994; Danysz and Archer, 1994). The transmission machinery at
K. Jellinger et al. (eds.), Ageing and Dementia © Springer-Verlag Wien 1998
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J. Kornhuber and J. Wiltfang
the glutamatergic synapse is quite complex. This also means that there is a gallery of targets for drugs designed to interact with the glutamatergic transmission. Glutamate acts on cell surface receptors classified as ionotropic or metabotropic. While metabotropic receptors mediate changes in intracellular signaling pathways, activation of ionotropic receptors opens ion channels and results in depolarization of the neuronal membrane. The differential affinity of the ionotropic glutamate receptors for different ligands has led to the classification into at least three major subtypes: N-methyl-D-aspartate (NMDA), kainate and a-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA) receptors. AMPA and kainate recepto
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