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The neuroprotectant properties of glutamate antagonists and antiglutamatergic drugs

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Abstract

In the slowly progressive neurodegenerative disorders like Parkinson’s disease and Alzheimer’s disease very different neuronal populations undergo degenerative processes, although, the cascades of cellular events leading to death are supposed to be similar. We suggest that the complex pattern of degeneration in Parkinson’s disease depends on two processes, a ‘primary neurodegeneration’ that takes place ir the striato-nigral dopamine neurons and a ‘secondary degeneration’, occurring in distant structures of the basal ganglia network.

For the purpose of explaining the regionally different expression of ‘primary neurodegeneration’ in different diseases, we postulate that the origin of neurodegeneration is associated with the local release of a neurotransmitter. For Parkinson’s disease this would mean that the metabolism of dopamine in the striatum, nucleus accumbens and presumably the pedunculopontine tegmental nucleus, together with one or more pathological factors contribute to the initial neurodegeneration. There are recent studies indicating that a transneuronal retrograde degeneration of the substantia nigra pars compacta neurons might be induced by a loss of function of dopaminergic synapses in the striatum. We have recently established an animal model of retrograde striato-nigral degeneration, where the assessment of markers for cellular stress is possible.

In Parkinson’s disease, several structures distal from the substantia nigra pars compacta undergo neuropathological changes, characterizing the ‘secondary neurodegeneration’. Our recent studies provide experimental evidence for a chronic cellular stress in these structures because of a relative or absolute glutamatergic overactivity due to the initial loss of dopaminergic innervation. Thus, a loss of dopamine transforms the basal ganglia to a ‘destructive network’. Both processes, the ‘primary’ and ‘secondary neurodegeneration’, affecting each other, characterize the progress of chronic neurodegeneration. From this point of view, we would further like to develop strategies for symptomatic amendment. Excitatory amino acids seem to be involved not only in the secondary processes of neurodegeneration, but also in initiation of the ‘primary degeneration’ of the substantia nigra pars compacta. Therefore, a reduction of glutamatergic overactivity constitutes a promising neuroprotective strategy. Especially the new antagonists of the NMDA-receptors with high affinity to the NR2B subunit of the receptor are in focus of our interest, since they reveal a favourable profile of side effects, therefore providing a promising tool for neuroprotection.

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Abbreviations

2-APV:

2-amino-phosphonovaleric acid

3-NP:

3-nitropropionic acid

4C3HPG:

(S)-4-carboxy-3-hydroxy-phenylglycine

ADCI:

(±)-5-aminocarbonyl-10,ll-dihydro-5H-dibenzo[a.b]cyclohepten-5,10-imine

AMPA:

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

CGP 37849:

(e)-2-amino-4-methyl-5-phosphono-3-pentanoic acid

CGP 39551:

(e)-2-amino-4-methyl-5-phosphono-3-pentanoic acid ethylester

CNQX:

6-cyano-7-nitro-quinoxaline-2,3-dione

CPP:

3-(2-carboxypiperazyl)propylphosphonic acid

CPPene:

SDZ EAA 494 (E)-4-(3-phosphonoprop-2-enyl)-piperzine-2-carboxylic acid

GYKI 52466:

1-(4′amino-phenyl)-4-methyl-7,8-methylen-dioxy-5H-2,3-benzodiazepine

L-CCG I:

(2S,1′ S,2′S)-carboxycyclopropylglycine

LY354740:

(+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate

MPP+ :

1-methyl-4-phenylpyridinium ion

MPTP:

1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine

NBQX:

2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)-quinoxaline

NMDA:

N-methyl-Daspartate

PPG:

(R,S)-4-phosphonophenylglycine

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    Vera Pedersen & Werner J. Schmidt

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Pedersen, V., Schmidt, W.J. The neuroprotectant properties of glutamate antagonists and antiglutamatergic drugs. neurotox res 2, 179–203 (2000). https://doi.org/10.1007/BF03033793

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