The antiparkinsonian agent budipine is an N-methyl-D-aspartate antagonist

Klockgether, Thomas; Jacobsen, Poul; Löschmann, Peter‐Andreas; Turski, Lechosław

doi:10.1007/bf02251200

Cited by 54 publications

(15 citation statements)

References 17 publications

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“…However, it is not clear whether the NMDA receptor blocking component of budipine is actually responsible for its antiparkinsonian effect. The budipine brain concentrations observed after single application of an effective dose were lower than those necessary to block the calcium channel of the NMDA receptor in vitro (Zech et al, 1985;Klockgether et al, 1993).…”

Section: Clinical Data Favouring a Role Of Excitatory Amino Acids In mentioning

confidence: 92%

“…The recently manufactured antiparkinsonian drug budipine (Byk-Gulden, Konstanz, Germany), which is at present in the III phase of clinical studies, has also turned out to be a non-competitive NMDA receptor antagonist which binds to the phencyclidine site (Klockgether et al, 1993). However, it is not clear whether the NMDA receptor blocking component of budipine is actually responsible for its antiparkinsonian effect.…”

Section: Clinical Data Favouring a Role Of Excitatory Amino Acids In mentioning

confidence: 98%

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The role of excitatory amino acids in experimental models of Parkinson's disease

Ossowska

1994

J Neural Transm Gen Sect

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The aim of this article was to review the recent literature on the role of excitatory amino acids in Parkinson's disease and in animal equivalents of parkinsonian symptoms. Effects of NMDA and AMPA antagonists on the reserpine-induced akinesia, catalepsy and rigidity, on the neuroleptic-induced catalepsy, on the turning behaviour of 6-OHDA-lesioned rats, as well as on the parkinsonian symptoms evoked by MPTP in monkeys were analysed. Moreover, the role of NMDA antagonists in Parkinson's disease was discussed. Data concerning the protective influence of these drugs on degenerative properties of methamphetamine, MPTP and 6-OHDOPA were also presented. On the basis of the above findings, the following conclusions may be drawn: (1) disturbances in the glutamatergic transmission in various brain structures seem to play a significant role in the development of symptoms of Parkinson's disease; (2) the NMDA-receptor blocking component may make a substantial contribution to the therapeutic effect of antiparkinsonian drugs; a similar contribution of AMPA-receptor blocking component has not been sufficiently documented, so far; (3) compounds blocking NMDA receptors may possibly prevent the development of Parkinson's disease; this presumption needs, however further studies; (4) side effects of NMDA receptor antagonists may be a limiting factor in the use of these compounds in humans.

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Section: Clinical Data Favouring a Role Of Excitatory Amino Acids In mentioning

confidence: 92%

Section: Clinical Data Favouring a Role Of Excitatory Amino Acids In mentioning

confidence: 98%

The role of excitatory amino acids in experimental models of Parkinson's disease

Ossowska

1994

J Neural Transm Gen Sect

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“…Although antagonists of postsynaptic ionotropic glutamate receptors can improve parkinsonian symptoms in PD patients and in animal models of PD (Klockgether et al, 1993;Kornhuber et al, 1994), these compounds are most effective as adjuncts to dopamine replacement therapy (Starr, 1995). Another approach would be to target metabotropic glutamate receptors (mGluRs), which are often localized presynaptically on glutamatergic terminals where…”

Section: Abstract: Substantia Nigra Pars Reticulata; Subthalamic Nucmentioning

confidence: 99%

Activation of Group II Metabotropic Glutamate Receptors Inhibits Synaptic Excitation of the Substantia Nigra Pars Reticulata

Bradley¹,

Marino²,

Wittmann

et al. 2000

J. Neurosci.

130

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Loss of nigrostriatal dopaminergic neurons in Parkinson's disease (PD) leads to increased activity of glutamatergic neurons in the subthalamic nucleus (STN). Recent studies reveal that the resultant increase in STN-induced excitation of basal ganglia output nuclei is responsible for the disabling motor impairment characteristic of PD. On the basis of this, it is possible that any manipulation that reduces activity at excitatory STN synapses onto basal ganglia output nuclei could be useful in the treatment of PD. We now report that group II metabotropic glutamate receptors (mGluRs) are presynaptically localized on STN terminals and that activation of these receptors inhibits excitatory transmission at STN synapses. In agreement with the hypothesis that this could provide a therapeutic benefit in PD, a selective agonist of group II mGluRs induces a dramatic reversal of catalepsy in a rat model of PD. These results raise the exciting possibility that selective agonists of group II mGluRs could provide an entirely new approach to the treatment of PD. These novel therapeutic agents would provide a noninvasive pharmacological treatment that does not involve the manipulation of dopaminergic systems, thus avoiding the problems associated with current therapies. Key words: substantia nigra pars reticulata; subthalamic nucleus; group II metabotropic glutamate receptors; Parkinson's disease; catalepsy; presynaptic inhibitionParkinson's disease (PD) is a common neurodegenerative disorder characterized by disabling motor impairments including tremor, rigidity, and bradykinesia. The primary pathological change giving rise to the symptoms of PD is the loss of dopaminergic neurons in the substantia nigra pars compacta that modulate the function of neurons in the striatum and other nuclei in the basal ganglia (BG) motor circuit. Currently, the most effective pharmacological agents for the treatment of PD include levodopa (L-DOPA), the immediate precursor of dopamine, and other drugs that replace the lost dopaminergic modulation of BG function (Poewe and Granata, 1997). Unfortunately, dopamine replacement therapy ultimately fails in most patients because of loss of efficacy with progression of the disease and severe motor and psychiatric side effects (Poewe et al., 1986). Because of this, a great deal of effort has been focused on developing new approaches for the treatment of PD.Recent studies reveal that loss of nigrostriatal dopamine neurons results in a series of neurophysiological changes that lead to overactivity of a critical nucleus in the BG motor circuit termed the subthalamic nucleus (STN). The STN contains glutamatergic projection neurons that provide the major excitatory input to the globus pallidus internal segment (GPi) and the substantia nigra pars reticulata (SNr), the major output nuclei of the basal ganglia. Increased activity of STN neurons leads to an increase in glutamate release at STN synapses onto GABAergic projection neurons in the output nuclei. This glutamate-mediated overexcitation of BG output ultima...

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“…Budipin besitzt aber zusätzlich eine schwache antimuskarinische Wirkung [54]. Budipin wird nach oraler Gabe vollständig resorbiert, hat aber aufgrund hoher Affinität zu inneren Organen eine Bioverfügbarkeit von nur 47%.…”

Section: Budipinunclassified

Medikamentöse Behandlung der idiopathischen Parkinson-Krankheit

Klockgether¹

2003

Der Nervenarzt

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Idiopathic Parkinson's disease (IPD) results from a largely selective degeneration of nigrostriatal dopaminergic neurons. Therefore, compounds which strengthen dopaminergic transmission in the striatum are the most important therapeutic approach. These include L-dopa, dopamine receptor agonists, selegeline, and entacapon. Since nigrostriatal degeneration leads to secondary alterations of cholinergic and glutamatergic transmission to the basal ganglia,nondopaminergic compounds such as anticholinergics and N-methyl-D-aspartate (NMDA) receptor antagonists are also used in the management of IPD. L-dopa is the most effective substance but after 3-5 years of L-dopa treatment, approximately half of all IPD patients develop fluctuations. Therefore, initial treatment with a dopamine receptor agonist is recommended.

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The antiparkinsonian agent budipine is an N-methyl-D-aspartate antagonist

Cited by 54 publications

References 17 publications

The role of excitatory amino acids in experimental models of Parkinson's disease

The role of excitatory amino acids in experimental models of Parkinson's disease

Activation of Group II Metabotropic Glutamate Receptors Inhibits Synaptic Excitation of the Substantia Nigra Pars Reticulata

Medikamentöse Behandlung der idiopathischen Parkinson-Krankheit

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