N-Methyl-d-Aspartate Antagonists in the Treatment of Parkinson's Disease

Greenamyre, J. Timothy; O’Brien, Christopher F.

doi:10.1001/archneur.1991.00530210109030

Cited by 215 publications

(88 citation statements)

References 55 publications

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“…Could calcium entry through NMDA receptors synergize with that through Cav1.3 channels engaged by pacemaking to create a metabolic tipping point for mitochondria? Excitotoxicity has long been hypothesized to be a factor in the etiology of PD (6,41,108), but the engagement of NMDA receptors and the elevation in cytosolic calcium concentration this brings about has been envisioned to be a relatively late stage event, coming only when cells were unable to maintain a stable, hyperpolarized membrane potential. Nevertheless, SNc DA neurons are pacemakers that do not have a stable hyperpolarized membrane potential when they are healthy, meaning that NMDA receptors should be more easily recruited.…”

Section: Cell-specific Factors In Pdmentioning

confidence: 99%

The Origins of Oxidant Stress in Parkinson's Disease and Therapeutic Strategies

Surmeier

Guzmán

Sánchez-Padilla

et al. 2011

Antioxidants & Redox Signaling

135

109

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Parkinson's disease (PD) is a major world-wide health problem afflicting millions of the aged population. Factors that act on most or all cell types (pan-cellular factors), particularly genetic mutations and environmental toxins, have dominated public discussions of disease etiology. Although there is compelling evidence supporting an association between disease risk and these factors, the pattern of neuronal pathology and cell loss is difficult to explain without cell-specific factors. This article focuses on recent studies showing that the neurons at greatest risk in PD-substantia nigra pars compacta dopamine neurons-have a distinctive physiological phenotype that could contribute to their vulnerability. The opening of L-type calcium channels during autonomous pacemaking results in sustained calcium entry into the cytoplasm of substantia nigra pars compacta dopamine neurons, resulting in elevated mitochondrial oxidant stress and susceptibility to toxins used to create animal models of PD. This cellspecific stress could increase the negative consequences of pan-cellular factors that broadly challenge either mitochondrial or proteostatic competence. The availability of well-tolerated, orally deliverable antagonists for L-type calcium channels points to a novel neuroprotective strategy that could complement current attempts to boost mitochondrial function in the early stages of the disease.

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Section: Cell-specific Factors In Pdmentioning

confidence: 99%

The Origins of Oxidant Stress in Parkinson's Disease and Therapeutic Strategies

Surmeier

Guzmán

Sánchez-Padilla

et al. 2011

Antioxidants & Redox Signaling

135

109

View full text Add to dashboard Cite

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“…Ketamine's anesthetic effect, on the other hand, is thought to result from its action as a non-competitive NMDA-receptor antagonist (Rudolph and Antkowiak, 2004;Wolff and Winstock, 2006), which ultimately results in depression of neuronal responses by interfering with the excitatory effects of glutamate (Anis et al, 1983;Wolff and Winstock, 2006). Ketamine may have effects similar to other NMDA antagonists such as amantadine which have effectively been used as adjuvant parkinsonian therapies (Papa et al, 1995;Papa and Chase, 1996;Blanchet et al, 1997Blanchet et al, , 2003Verhagen et al, 1998;Luginger et al, 2000), potentially acting at the level of the STN to reduce glutamatergic output from this structure (Greenamyre and O'Brien, 1991;Allers et al, 2005).…”

Section: Comparison Of the Neurological Effects Of Urethane And Ketammentioning

confidence: 99%

Altered neuronal activity relationships between the pedunculopontine nucleus and motor cortex in a rodent model of Parkinson's disease

Aravamuthan

Bergstrom

French

et al. 2008

Experimental Neurology

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The pedunculopontine nucleus (PPN) is a new deep brain stimulation (DBS) target for Parkinson's disease (PD), but little is known about PPN firing pattern alterations in PD. The anesthetized rat is a useful model for investigating the effects of dopamine loss on the transmission of oscillatory cortical activity through basal ganglia structures. After dopamine loss, synchronous oscillatory activity emerges in the subthalamic nucleus and substantia nigra pars reticulata in phase with cortical slow oscillations. To investigate the impact of dopamine cell lesion-induced changes in basal ganglia output on activity in the PPN, this study examines PPN spike timing with reference to motor cortex (MCx) local field potential (LFP) activity in urethane-and ketamine-anesthetized rats. Seven -ten days after unilateral 6-hydroxydopamine lesion of the medial forebrain bundle, spectral power in PPN spike trains and coherence between PPN spiking and PPN LFP activity increased in the ∼1 Hz range in urethane-anesthetized rats. PPN spike timing also changed from firing predominantly in-phase with MCx slow oscillations in the intact urethane-anesthetized rat to firing predominantly antiphase to MCx oscillations in the hemi-parkinsonian rat. These changes were not observed in the ketamine-anesthetized preparation. These observations suggest that dopamine loss alters PPN spike timing by increasing inhibitory oscillatory input to the PPN from basal ganglia output nuclei, a phenomenon that may be relevant to motor dysfunction and PPN DBS efficacy in PD patients.

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“…In the CA1 region of the hippocampus, activation of these receptors is known to be required for induction of long term potentiation (LTP), a cellular process proposed by many as a possible mechanism of memory formation. Aberrant NMDA receptor function can result in cell death and may have implications in pathophysiologic disorders such as Parkinson's disease and epilepsy as well as age-related dementias like Alzheimer's disease (7)(8)(9)(10)(11). NMDA receptors are heteromeric assemblies of NR1 and NR2 subunits.…”

Section: Nmdamentioning

confidence: 99%

Tyrosine Dephosphorylation and Ethanol Inhibition of N-Methyl-d-aspartate Receptor Function

Alvestad¹,

Grosshans²,

Coultrap³

et al. 2003

Journal of Biological Chemistry

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NMDA1 receptors are ionotropic glutamate receptors that mediate calcium and sodium entry into neurons. In the CA1 region of the hippocampus, activation of these receptors is known to be required for induction of long term potentiation (LTP), a cellular process proposed by many as a possible mechanism of memory formation. Aberrant NMDA receptor function can result in cell death and may have implications in pathophysiologic disorders such as Parkinson's disease and epilepsy as well as age-related dementias like Alzheimer's disease (7-11). NMDA receptors are heteromeric assemblies of NR1 and NR2 subunits. The NR1 family is composed of a single gene, which can be alternatively spliced to generate eight theoretical splice variants (12). The NR2 family includes four genes, each encoding a unique subunit: NR2A, NR2B, NR2C, and NR2D (13). A third gene family, NR3, has been discovered, but the function of these subunits is not well understood. Whereas the NR1 subunit is required for a functional channel, differential incorporation of NR2 subunits regulates receptor function. The NR2 subunits, particularly NR2A and NR2B, have been shown to influence the sensitivity of NMDA receptors to ethanol block in cultured neurons as wells as transfected HEK293 cells and oocytes (14 -17). More recent studies have indicated that NR1 subunits may also play a key role in mediating the effects of ethanol on channel activity (18 -20).Ethanol is known to have widespread effects on the central nervous system. Ethanol inhibits transmission at the NMDAR subtype of glutamatergic excitatory synapses and enhances inhibitory GABAergic synaptic transmission. In addition, we and others have demonstrated that ethanol blocks LTP in the hippocampus (6,(21)(22)(23). Given that NMDA receptors are both required for induction of LTP and inhibited by ethanol, it is likely that inhibition of LTP by ethanol in the hippocampus is due, at least in part, to inhibition of NMDA receptors. The molecular mechanisms of this inhibition however, remain unknown.One hypothesis that we favor is that ethanol may inhibit the NMDAR by reducing its phosphorylation. Indeed, ethanol has been shown to enhance protein-tyrosine phosphatase activity and also inhibit receptor tyrosine kinase activity (24, 25). Moreover, previous studies suggest that Fyn, a member of the Src family of tyrosine kinases, may be a key player in regulating the sensitivity of NMDARs to ethanol in the hippocampus (26 -28

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N-Methyl-d-Aspartate Antagonists in the Treatment of Parkinson's Disease

Cited by 215 publications

References 55 publications

The Origins of Oxidant Stress in Parkinson's Disease and Therapeutic Strategies

The Origins of Oxidant Stress in Parkinson's Disease and Therapeutic Strategies

Altered neuronal activity relationships between the pedunculopontine nucleus and motor cortex in a rodent model of Parkinson's disease

Tyrosine Dephosphorylation and Ethanol Inhibition of N-Methyl-d-aspartate Receptor Function

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