The N‐Methyl‐D‐Aspartate Antagonist MK‐801 Fails to Protect Dopaminergic Neurons from 1‐Methyl‐4‐ Phenylpyridinium Toxicity In Vitro

Finiels-Marlier, Françoise; Marini, Ann M.; Williams, P.B.; Paul, Steven M.

doi:10.1111/j.1471-4159.1993.tb13431.x

Cited by 31 publications

(13 citation statements)

References 16 publications

(13 reference statements)

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“…2). Because CGNs express NMDA receptors and the neurotoxic effects of MPP ϩ could be mediated by an interaction with these glutamate receptors, we decided to test the effects of MK801, a selective NMDA receptor antagonist in our experimental conditions (Finiels-Marlier et al, 1993). Our results indicate that this selective compound did not prevent MPP ϩ -induced DNA fragmentation in CGNs (Fig.…”

Section: Role Of Cysteine Proteases 3-ma and Mk-801 In Mpp ؉ -Inducementioning

confidence: 80%

Inhibition of cyclin-dependent kinases is neuroprotective in 1-methyl-4-phenylpyridinium-induced apoptosis in neurons

et al. 2007

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the antioxidant vitamin E (vit E) increases neuronal cell viability and attenuates apoptosis induced by MPP؉ . Moreover, the expression levels of cyclin D and E2F-1 induced by this parkinsonian neurotoxin were also attenuated by vit E. Since, the broad-spectrum caspase inhibitor zVAD-fmk did not attenuate MPP ؉ -induced apoptosis in CGNs, our data provide a caspase-independent mechanism mediated by neuronal reentry in the cell cycle and increased expression of the pro-apoptotic transcription factor E2F-1. Our results also suggest a potential role of oxidative stress in neuronal reentry in the cell cycle mediated by MPP ؉ . Finally, our data further support the therapeutic potential of flavopiridol, for the treatment of Parkinson's disease.

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Section: Role Of Cysteine Proteases 3-ma and Mk-801 In Mpp ؉ -Inducementioning

confidence: 80%

Inhibition of cyclin-dependent kinases is neuroprotective in 1-methyl-4-phenylpyridinium-induced apoptosis in neurons

et al. 2007

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“…NMDA receptor involvement has been reported to contribute to dopaminergic cell death in brain slices and mesencephalic cultures derived from rat after administration of metabolic inhibitors, including MPP ϩ , in some studies (Zeevalk et al, 1995;McNaught and Jenner, 1999;Bywood and Johnson, 2003) but not in others (Michel and Agid, 1992;Finiels-Marlier et al, 1993;Sawada et al, 1996). As species differences could not account for the respective changes, we reasoned that differences in experimental preparations might underlie these disparate findings.…”

Section: Discussionmentioning

confidence: 84%

Relationship between NMDA receptor expression and MPP⁺ toxicity in cultured dopaminergic cells

Church

Hewett

2003

J of Neuroscience Research

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It has been suggested that excitotoxicity could be contributing to dopamine cell loss after methylphenylpyridinium ion (MPP+) exposure, although the literature regarding this is contradictory. Given that in cell culture excitotoxicity has been reported to be dependent on culture age, we postulated that these discrepant results might be explained by a difference in developmental expression of N-methyl-D-aspartate (NMDA) receptors. To test this, mesencephalic cells were cultured and the number of dopaminergic neurons (tyrosine hydroxylase-immunoreactive cells [TH-IR] cells) expressing the NMDA R1 subunit (NR1) was determined using double-label immunofluorescence microscopy. An increase in the percentage of TH-IR cells expressing NR1 occurred over time in culture and this correlated with the toxicity of NMDA. At 7 days in vitro (DIV 7), only 17% (n=167 cells/4 experiments) of TH-IR cells expressed NR1 and these cells were insensitive to NMDA toxicity. This increased to 80% (n=254 cells/6 experiments) by DIV 11 and cultures were now susceptible to NMDA-induced injury. Cultures grown for either 7 or 11 days were treated for 48 hr with increasing concentrations of MPP= (0.5-20 microM) and the loss of dopaminergic neurons was determined by cell counting. Cultures at DIV 7 were more sensitive to MPP= than 11-day-old cultures (LD50= approximately 0.75 microM vs. 15 microM, respectively). Co-exposure to MK-801 (5 microM) did not protect against MPP+ toxicity in young cultures, but attenuated MPP+ toxicity in the older cultures, becoming statistically significant at 20 microM MPP+. These data indicate that the activation of NMDA receptors is not required for, but can contribute to, MPP(+)-induced neurodegeneration of dopaminergic cells in culture.

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“…However, the noncompetitive NMDA receptor antagonist, MK-801, failed to protect rats against MPP + and mice against MPTP neurotoxicity (15)(16)(17). The observed neuroprotective effect of ketamine may also be mediated by its dopamine D 2 receptor agonist action, as is the case for other agonists such as pramipexole reported to be neuroprotective against MPTP and 6-OHDA lesions (18).…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective effect of ketamine/xylazine on two rat models of Parkinson's disease

Ferro¹,

Angelucci²,

Anselmo-Franci³

et al. 2007

Braz J Med Biol Res

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There is a great concern in the literature for the development of neuroprotectant drugs to treat Parkinson's disease. Since anesthetic drugs have hyperpolarizing properties, they can possibly act as neuroprotectants. In the present study, we have investigated the neuroprotective effect of a mixture of ketamine (85 mg/kg) and xylazine (3 mg/kg) (K/X) on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6-hydroxydopamine (6-OHDA) rat models of Parkinson's disease. The bilateral infusion of MPTP (100 µg/side) or 6-OHDA (10 µg/side) into the substantia nigra pars compacta of adult male Wistar rats under thiopental anesthesia caused a modest (~67%) or severe (~91%) loss of tyrosine hydroxylase-immunostained cells, respectively. On the other hand, an apparent neuroprotective effect was observed when the rats were anesthetized with K/X, infused 5 min before surgery. This treatment caused loss of only 33% of the nigral tyrosine hydroxylase-immunostained cells due to the MPTP infusion and 51% due to the 6-OHDA infusion. This neuroprotective effect of K/X was also suggested by a less severe reduction of striatal dopamine levels in animals treated with these neurotoxins. In the working memory version of the Morris water maze task, both MPTP-and 6-OHDA-lesioned animals spent nearly 10 s longer to find the hidden platform in the groups where the neurotoxins were infused under thiopental anesthesia, compared to control animals. This amnestic effect was not observed in rats infused with the neurotoxins under K/X anesthesia. These results suggest that drugs with a pharmacological profile similar to that of K/X may be useful to delay the progression of Parkinson's disease.

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The N‐Methyl‐D‐Aspartate Antagonist MK‐801 Fails to Protect Dopaminergic Neurons from 1‐Methyl‐4‐ Phenylpyridinium Toxicity In Vitro

Cited by 31 publications

References 16 publications

Inhibition of cyclin-dependent kinases is neuroprotective in 1-methyl-4-phenylpyridinium-induced apoptosis in neurons

Inhibition of cyclin-dependent kinases is neuroprotective in 1-methyl-4-phenylpyridinium-induced apoptosis in neurons

Relationship between NMDA receptor expression and MPP⁺ toxicity in cultured dopaminergic cells

Neuroprotective effect of ketamine/xylazine on two rat models of Parkinson's disease

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The N‐Methyl‐D‐Aspartate Antagonist MK‐801 Fails to Protect Dopaminergic Neurons from 1‐Methyl‐4‐ Phenylpyridinium Toxicity In Vitro

Cited by 31 publications

References 16 publications

Inhibition of cyclin-dependent kinases is neuroprotective in 1-methyl-4-phenylpyridinium-induced apoptosis in neurons

Inhibition of cyclin-dependent kinases is neuroprotective in 1-methyl-4-phenylpyridinium-induced apoptosis in neurons

Relationship between NMDA receptor expression and MPP+ toxicity in cultured dopaminergic cells

Neuroprotective effect of ketamine/xylazine on two rat models of Parkinson's disease

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Relationship between NMDA receptor expression and MPP⁺ toxicity in cultured dopaminergic cells