NMDA receptor blockade reverses motor response alterations induced by levodopa

Engber, Thomas M.; Papa, Stella M.; Boldry, Robert C.; Chase, Thomas N.

doi:10.1097/00001756-199412000-00045

Cited by 110 publications

(41 citation statements)

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“…Hence, development of NMDA receptor antagonists for therapeutic use in PD has been pursued actively during the past few years. But these glutamate antagonists have very low effectiveness, and a plethora of side effects that have limited their clinical utility as neuroprotectants (Sonsalla et al, 1992;Engber et al, 1994;Nilsson et al, 1997;Li et al, 2002). An alternate strategy is to attenuate the excitotoxic response in the basal ganglia by indirectly modulating other interacting neurotransmitter systems.…”

Section: Discussionmentioning

confidence: 99%

“…Glutamate binds to a variety of excitatory amino acid receptors, especially the NMDA receptor, leading to prolonged and excessive depolarization and neuronal activation resulting in the death of target neurons (Choi, 1988;Lynch and Dawson, 1994). Consequently, NMDA receptor blockade in PD research has been actively pursued over the past decade, but to date has been limited by the side effects of the glutamate antagonists (Nilsson et al, 1997;Li et al, 2002) and their mixed effectiveness (Sonsalla et al, 1992;Engber et al, 1994).…”

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confidence: 99%

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5-Hydroxytryptamine 1A Receptor Activation Protects againstN-Methyl-d-aspartate-Induced Apoptotic Cell Death in Striatal and Mesencephalic Cultures

Madhavan

Freed

Anantharam

et al. 2002

J Pharmacol Exp Ther

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Apoptosis and glutamate-mediated excitotoxicity may play a role in the pathogenesis of many neurodegenerative disorders, including Parkinson's disease (PD). In the present study, we investigated whether stimulation of the 5-hydroxytryptamine 1A (5-HT1A) receptor attenuates N-methyl-D-aspartate-(NMDA) and 1-methyl-4-phenylpyridinium (MPP ϩ )-induced apoptotic cell death in cell culture models. A brief exposure (20 min) of M213-2O striatal cells to NMDA and glutamate produced a delayed increase in caspase-3 activity and DNA fragmentation in a dose-and time-dependent manner. NMDA-induced caspase-3 activity and DNA fragmentation were almost completely blocked by the 5-HT1A agonists 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and (R)-5-fluoro-8 hydroxy-2-(dipropylamino)-tetralin (R-UH-301). Additionally, the protective effects of 8-OH-DPAT and R-UH-301 on NMDA-induced caspase-3 activation and apoptosis were reversed by pretreatment with the 5-HT1A antagonists N- [2-[4-(2-methoxyphenyl(WAY 100635) and S-UH-301, respectively. Similarly, doseand time-dependent increases in caspase-3 activity and DNA fragmentation were observed in rat primary mesencephalic neurons after a brief exposure to NMDA and glutamate. Caspase-3 activation and DNA fragmentation in primary mesencephalic neurons were almost completely inhibited by 8-OH-DPAT. This neuroprotective effect of 8-OH-DPAT was reversed by WAY 100635. Additionally, 8-OH-DPAT blocked tyrosine hydroxylase (TH)-positive cell death after NMDA exposure and also almost completely attenuated the NMDA-induced Ca 2ϩ influx in primary mesencephalic cultures. Furthermore, 8-OH-DPAT and R-UH-301 blocked apoptotic cell death in the primary mesencephalic neurons that were exposed to the Parkinsonian toxin MPP ϩ . Together, these results suggest that 5-HT1A receptor stimulation may be a promising pharmacological approach in the development of neuroprotective agents for PD.Parkinson's disease (PD) is a major neurodegenerative disorder with a lifetime incidence of 1 to 2%. The drug L-DOPA has been the gold standard PD treatment for more than three decades now and can bring considerable relief from the debilitating symptoms of the disease. However, its long-term use has several limitations, including severe fluctuations in effectiveness and drug-induced involuntary movements (Fahn, 1999;Carlsson, 2002). Importantly, L-DOPA simply compensates for the dopamine deficiency in Parkinson's patients and fails to attenuate the progression of the disease. Hence, novel neuroprotective agents designed to interfere with the basic pathogenic mechanism of cell death in PD are clearly needed.Excitotoxic mechanisms may contribute to the nigrostriatal degeneration in PD (Greenamyre, 1993;Olanow and Tatton, 1999). Glutamate binds to a variety of excitatory amino acid receptors, especially the NMDA receptor, leading to prolonged and excessive depolarization and neuronal activation resulting in the death of target neurons (Choi, 1988;

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

5-Hydroxytryptamine 1A Receptor Activation Protects againstN-Methyl-d-aspartate-Induced Apoptotic Cell Death in Striatal and Mesencephalic Cultures

Madhavan

Freed

Anantharam

et al. 2002

J Pharmacol Exp Ther

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“…In animal models of Parkinson's disease, antagonists of NMDA receptors substantially potentiate the short-term therapeutic effect of dopaminergic agents (Klockgether and Turski, 1990;Morelli et al, 1992;Papa et al, 1993;Kaur and Starr, 1997) and are effective in attenuating the abnormal motor behaviors produced by chronic dopaminergic treatment (Papa et al, 1995;Marin et al, 1996;Blanchet et al, 1997). Recent evidence suggests that the basis for the development of these abnormal motor behaviors may be that long-term treatment with dopaminergic agents modifies the properties of striatal NMDA receptors (Engber et al, 1994;Papa et al, 1995;Marin et al, 1996;Papa and Chase, 1996;Chase et al, 1998).…”

Section: Abstract: Glutamate Receptor; Nmda Receptor; Dopamine Recepmentioning

confidence: 99%

Dopamine D1 Receptor-Dependent Trafficking of Striatal NMDA Glutamate Receptors to the Postsynaptic Membrane

2001

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Recent work has shown substantial alterations in NMDA receptor subunit expression, assembly, and phosphorylation in the dopamine-depleted striatum of a rodent 6-hydroxydopamine model of Parkinson's disease. These modifications are hypothesized to result from the trafficking of NMDA receptors between subcellular compartments. Here we show that in rat striatal tissues the NR2A and NR2B subunits in the synaptosomal membrane, and not those in the light membrane and synaptic vesicle-enriched compartments, are tyrosine phosphorylated. The dopamine D1 receptor agonist SKF-82958 produces (1) an increase in NR1, NR2A, and NR2B proteins in the synaptosomal membrane fraction; (2) a decrease in NR1, NR2A, and NR2B proteins in the light membrane and synaptic vesicleenriched fractions; and (3) an increase in the tyrosine phosphorylation of NR2A and NR2B in the synaptosomal membrane compartment. The protein phosphatase inhibitor pervanadate reproduces the alterations in subcellular distribution and phosphorylation, whereas the effects of the dopamine D1 receptor agonist are blocked by genistein, a protein tyrosine kinase inhibitor. Dopamine D1 receptor agonist treatment does not change the subcellular distribution of the AMPA receptor subunits GluR1 or GluR2/3 in the striatum and has no effect on cortical or cerebellar NMDA receptor subunits. These data reveal a rapid dopamine D1 receptor-and tyrosine kinasedependent trafficking of striatal NMDA receptors between intracellular and postsynaptic sites. The subcellular trafficking of striatal NMDA receptors may play a significant role both in the pathogenesis of Parkinson's disease and in the development of adverse effects of chronic dopaminergic therapy in parkinsonian patients.

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“…С одной стороны, его эффективность была продемонстрирована в ряде доклинических исследовани-ях на животных моделях [22,23], затем в открытых [24] и двойных слепых клинических исследованиях развернутых стадий БП [25]. Были получены следующие результаты: ■ Прием амантадина (300 мг/д) уменьшал выраженность дискинезий у 60-70% пациентов [26].…”

Section: влияние на моторные осложнения терапии леводопойunclassified

Amantadines: Experience of Application for Parkinson Disease

Пилипович¹,

Golubev²

2016

Med. sov.

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NMDA receptor blockade reverses motor response alterations induced by levodopa

Cited by 110 publications

References 0 publications

5-Hydroxytryptamine 1A Receptor Activation Protects againstN-Methyl-d-aspartate-Induced Apoptotic Cell Death in Striatal and Mesencephalic Cultures

5-Hydroxytryptamine 1A Receptor Activation Protects againstN-Methyl-d-aspartate-Induced Apoptotic Cell Death in Striatal and Mesencephalic Cultures

Dopamine D1 Receptor-Dependent Trafficking of Striatal NMDA Glutamate Receptors to the Postsynaptic Membrane

Amantadines: Experience of Application for Parkinson Disease

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