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Inhibition of N-methyl-D-aspartate receptors increases paraoxon-induced apoptosis in cultured neurons.
Toxicol Appl Pharmacol. 2005 Oct 01; 208(1):57-67.TA

Abstract

Organophosphorus (OP) compounds, used as insecticides and chemical warfare agents, are potent neurotoxins. We examined the neurotoxic effect of paraoxon (O,O-diethyl O-p-nitrophenyl phosphate), an organophosphate compound, and the role of NMDA receptors as a mechanism of action in cultured cerebellar granule cells. Paraoxon is neurotoxic to cultured rat cerebellar granule cells in a time- and concentration-dependent manner. Cerebellar granule cells are less sensitive to the neurotoxic effects of paraoxon on day in vitro (DIV) 4 than neurons treated on DIV 8. Surprisingly, the N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, enhances paraoxon-mediated neurotoxicity suggesting that NMDA receptors may play a protective role. Pretreatment with a subtoxic concentration of N-methyl-D-aspartate (NMDA) [100 microM] protects about 40% of the vulnerable neurons that would otherwise die from paraoxon-induced neurotoxicity. Moreover, addition of a neuroprotective concentration of NMDA 3 h after treatment with paraoxon provides the same level of protection. Because paraoxon-mediated neuronal cell death is time-dependent, we hypothesized that apoptosis may be involved. Paraoxon increases apoptosis about 10-fold compared to basal levels. The broad-spectrum caspase inhibitor (Boc-D-FMK) and the caspase-9-specific inhibitor (Z-LEHD-FMK) protect against paraoxon-mediated apoptosis, paraoxon-stimulated caspase-3 activity and neuronal cell death. MK-801 increases, whereas NMDA blocks paraoxon-induced apoptosis and paraoxon-stimulated caspase-3 activity. These results suggest that activation of NMDA receptors protect neurons against paraoxon-induced neurotoxicity by blocking apoptosis initiated by paraoxon.

Authors+Show Affiliations

Department of Neurology, Uniformed Services University of the Health Sciences, Building A, Room 1036, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

16164961

Citation

Wu, Xuan, et al. "Inhibition of N-methyl-D-aspartate Receptors Increases Paraoxon-induced Apoptosis in Cultured Neurons." Toxicology and Applied Pharmacology, vol. 208, no. 1, 2005, pp. 57-67.
Wu X, Tian F, Okagaki P, et al. Inhibition of N-methyl-D-aspartate receptors increases paraoxon-induced apoptosis in cultured neurons. Toxicol Appl Pharmacol. 2005;208(1):57-67.
Wu, X., Tian, F., Okagaki, P., & Marini, A. M. (2005). Inhibition of N-methyl-D-aspartate receptors increases paraoxon-induced apoptosis in cultured neurons. Toxicology and Applied Pharmacology, 208(1), 57-67.
Wu X, et al. Inhibition of N-methyl-D-aspartate Receptors Increases Paraoxon-induced Apoptosis in Cultured Neurons. Toxicol Appl Pharmacol. 2005 Oct 1;208(1):57-67. PubMed PMID: 16164961.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of N-methyl-D-aspartate receptors increases paraoxon-induced apoptosis in cultured neurons. AU - Wu,Xuan, AU - Tian,Feng, AU - Okagaki,Peter, AU - Marini,Ann M, PY - 2004/11/19/received PY - 2005/01/10/revised PY - 2005/01/27/accepted PY - 2005/9/17/pubmed PY - 2006/5/5/medline PY - 2005/9/17/entrez SP - 57 EP - 67 JF - Toxicology and applied pharmacology JO - Toxicol Appl Pharmacol VL - 208 IS - 1 N2 - Organophosphorus (OP) compounds, used as insecticides and chemical warfare agents, are potent neurotoxins. We examined the neurotoxic effect of paraoxon (O,O-diethyl O-p-nitrophenyl phosphate), an organophosphate compound, and the role of NMDA receptors as a mechanism of action in cultured cerebellar granule cells. Paraoxon is neurotoxic to cultured rat cerebellar granule cells in a time- and concentration-dependent manner. Cerebellar granule cells are less sensitive to the neurotoxic effects of paraoxon on day in vitro (DIV) 4 than neurons treated on DIV 8. Surprisingly, the N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, enhances paraoxon-mediated neurotoxicity suggesting that NMDA receptors may play a protective role. Pretreatment with a subtoxic concentration of N-methyl-D-aspartate (NMDA) [100 microM] protects about 40% of the vulnerable neurons that would otherwise die from paraoxon-induced neurotoxicity. Moreover, addition of a neuroprotective concentration of NMDA 3 h after treatment with paraoxon provides the same level of protection. Because paraoxon-mediated neuronal cell death is time-dependent, we hypothesized that apoptosis may be involved. Paraoxon increases apoptosis about 10-fold compared to basal levels. The broad-spectrum caspase inhibitor (Boc-D-FMK) and the caspase-9-specific inhibitor (Z-LEHD-FMK) protect against paraoxon-mediated apoptosis, paraoxon-stimulated caspase-3 activity and neuronal cell death. MK-801 increases, whereas NMDA blocks paraoxon-induced apoptosis and paraoxon-stimulated caspase-3 activity. These results suggest that activation of NMDA receptors protect neurons against paraoxon-induced neurotoxicity by blocking apoptosis initiated by paraoxon. SN - 0041-008X UR - https://www.unboundmedicine.com/medline/citation/16164961/Inhibition_of_N_methyl_D_aspartate_receptors_increases_paraoxon_induced_apoptosis_in_cultured_neurons_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(05)00038-4 DB - PRIME DP - Unbound Medicine ER -