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Preferential inhibition by antidiarrheic 2-methoxy-4-methylphenol of Ca(2+) influx across acquired N-methyl-D-aspartate receptor channels composed of NR1/NR2B subunit assembly.
J Neurosci Res. 2010 Aug 15; 88(11):2483-93.JN

Abstract

In our previous studies, particular phenolic ingredients, such as 2-methoxy-4-methylphenol (2M4MP), of the antidiarrheic drug wood creosote significantly prevented cell death by both hydrogen peroxide and glutamate in cultured rat hippocampal neurons. In this study, we further evaluated the pharmacological properties of 2M4MP on Ca(2+) influx across native and acquired N-methyl-D-aspartate (NMDA) receptor (NMDAR) channels. The addition of 2M4MP significantly prevented the loss of cellular viability and the increase in intracellular free Ca(2+) levels as determined by Fluo-3 in cultured rat hippocampal neurons briefly exposed to NMDA. Brief exposure to NMDA also led to a marked increase in mitochondrial free Ca(2+) levels determined by Rhod-2, in addition to intracellular free Ca(2+) levels, in HEK293 cells expressing either NR1/NR2A or NR1/NR2B subunit channels. The further addition of the general NMDAR channel blocker dizocilpine similarly inhibited the increase of intracellular Ca(2+) levels by NMDA in both types of acquired NMDAR channels, whereas the NR2B subunit selective antagonist ifenprodil drastically inhibited the increase by NMDA in HEK293 cells expressing NR1/NR2B, but not NR1/NR2A, subunits. Similarly, 2M4MP significantly and selectively inhibited the NMDA-induced influx of Ca(2+) across acquired NR1/NR2B channels in a concentration-dependent manner. Moreover, prior daily oral administration of 2M4MP significantly reduced the infarct volume in the ipsilateral cerebral hemisphere in rats with middle cerebral artery occlusion 1 day after reperfusion. These results suggest that 2M4MP may protect neurons from excitotoxicity through preferential inhibition of Ca(2+) influx across NMDAR channels composed of NR1/NR2B subunits.

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Authors+Show Affiliations

Nakamichi N
Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School of Natural Science and Technology, Kanazawa, Ishikawa, Japan.
Fukumori R
No affiliation info available
Takarada T
No affiliation info available
Kambe Y
No affiliation info available
Yamamoto T
No affiliation info available
Matsushima N
No affiliation info available
Moriguchi N
No affiliation info available
Yoneda Y
No affiliation info available

MeSH

AnimalsBlotting, WesternCalciumCell LineCell SurvivalCells, CulturedCresolsHippocampusHumansInfarction, Middle Cerebral ArteryMitochondriaNeuronsNeuroprotective AgentsRatsReceptors, N-Methyl-D-Aspartate

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20623618

Citation

Nakamichi, Noritaka, et al. "Preferential Inhibition By Antidiarrheic 2-methoxy-4-methylphenol of Ca(2+) Influx Across Acquired N-methyl-D-aspartate Receptor Channels Composed of NR1/NR2B Subunit Assembly." Journal of Neuroscience Research, vol. 88, no. 11, 2010, pp. 2483-93.
Nakamichi N, Fukumori R, Takarada T, et al. Preferential inhibition by antidiarrheic 2-methoxy-4-methylphenol of Ca(2+) influx across acquired N-methyl-D-aspartate receptor channels composed of NR1/NR2B subunit assembly. J Neurosci Res. 2010;88(11):2483-93.
Nakamichi, N., Fukumori, R., Takarada, T., Kambe, Y., Yamamoto, T., Matsushima, N., Moriguchi, N., & Yoneda, Y. (2010). Preferential inhibition by antidiarrheic 2-methoxy-4-methylphenol of Ca(2+) influx across acquired N-methyl-D-aspartate receptor channels composed of NR1/NR2B subunit assembly. Journal of Neuroscience Research, 88(11), 2483-93. https://doi.org/10.1002/jnr.22399
Nakamichi N, et al. Preferential Inhibition By Antidiarrheic 2-methoxy-4-methylphenol of Ca(2+) Influx Across Acquired N-methyl-D-aspartate Receptor Channels Composed of NR1/NR2B Subunit Assembly. J Neurosci Res. 2010 Aug 15;88(11):2483-93. PubMed PMID: 20623618.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Preferential inhibition by antidiarrheic 2-methoxy-4-methylphenol of Ca(2+) influx across acquired N-methyl-D-aspartate receptor channels composed of NR1/NR2B subunit assembly. AU - Nakamichi,Noritaka, AU - Fukumori,Ryo, AU - Takarada,Takeshi, AU - Kambe,Yuki, AU - Yamamoto,Tomomi, AU - Matsushima,Nobuyuki, AU - Moriguchi,Nobuaki, AU - Yoneda,Yukio, PY - 2010/7/13/entrez PY - 2010/7/14/pubmed PY - 2010/10/21/medline SP - 2483 EP - 93 JF - Journal of neuroscience research JO - J Neurosci Res VL - 88 IS - 11 N2 - In our previous studies, particular phenolic ingredients, such as 2-methoxy-4-methylphenol (2M4MP), of the antidiarrheic drug wood creosote significantly prevented cell death by both hydrogen peroxide and glutamate in cultured rat hippocampal neurons. In this study, we further evaluated the pharmacological properties of 2M4MP on Ca(2+) influx across native and acquired N-methyl-D-aspartate (NMDA) receptor (NMDAR) channels. The addition of 2M4MP significantly prevented the loss of cellular viability and the increase in intracellular free Ca(2+) levels as determined by Fluo-3 in cultured rat hippocampal neurons briefly exposed to NMDA. Brief exposure to NMDA also led to a marked increase in mitochondrial free Ca(2+) levels determined by Rhod-2, in addition to intracellular free Ca(2+) levels, in HEK293 cells expressing either NR1/NR2A or NR1/NR2B subunit channels. The further addition of the general NMDAR channel blocker dizocilpine similarly inhibited the increase of intracellular Ca(2+) levels by NMDA in both types of acquired NMDAR channels, whereas the NR2B subunit selective antagonist ifenprodil drastically inhibited the increase by NMDA in HEK293 cells expressing NR1/NR2B, but not NR1/NR2A, subunits. Similarly, 2M4MP significantly and selectively inhibited the NMDA-induced influx of Ca(2+) across acquired NR1/NR2B channels in a concentration-dependent manner. Moreover, prior daily oral administration of 2M4MP significantly reduced the infarct volume in the ipsilateral cerebral hemisphere in rats with middle cerebral artery occlusion 1 day after reperfusion. These results suggest that 2M4MP may protect neurons from excitotoxicity through preferential inhibition of Ca(2+) influx across NMDAR channels composed of NR1/NR2B subunits. SN - 1097-4547 UR - https://www.unboundmedicine.com/medline/citation/20623618/Preferential_inhibition_by_antidiarrheic_2_methoxy_4_methylphenol_of_Ca_2+__influx_across_acquired_N_methyl_D_aspartate_receptor_channels_composed_of_NR1/NR2B_subunit_assembly_ L2 - https://doi.org/10.1002/jnr.22399 DB - PRIME DP - Unbound Medicine ER -