Preferential inhibition by antidiarrheic 2-methoxy-4-methylphenol of Ca2+ influx across acquired N-methyl-D-aspartate receptor channels composed of NR1/NR2B subunit assembly

Noritaka Nakamichi, Ryo Fukumori, Takeshi Takarada, Yuki Kambe, Tomomi Yamamoto, Nobuyuki Matsushima, Nobuaki Moriguchi, Yukio Yoneda

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 Ca2+ 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 Ca2+ 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 Ca2+ levels determined by Rhod-2, in addition to intracellular free Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ influx across NMDAR channels composed of NR1/NR2B subunits.

Original languageEnglish
Pages (from-to)2483-2493
Number of pages11
JournalJournal of Neuroscience Research
Volume88
Issue number11
DOIs
Publication statusPublished - Aug 15 2010
Externally publishedYes

Fingerprint

N-Methyl-D-Aspartate Receptors
N-Methylaspartate
HEK293 Cells
Neurons
Creosote
Dizocilpine Maleate
Middle Cerebral Artery Infarction
Cerebrum
Hydrogen Peroxide
Reperfusion
Oral Administration
creosol
Glutamic Acid
Cell Death
Pharmacology
Pharmaceutical Preparations

Keywords

  • Antidiarrheic
  • Ca influx
  • NMDA receptor
  • NR2A subunit
  • NR2B subunit

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

Preferential inhibition by antidiarrheic 2-methoxy-4-methylphenol of Ca2+ influx across acquired N-methyl-D-aspartate receptor channels composed of NR1/NR2B subunit assembly. / Nakamichi, Noritaka; Fukumori, Ryo; Takarada, Takeshi; Kambe, Yuki; Yamamoto, Tomomi; Matsushima, Nobuyuki; Moriguchi, Nobuaki; Yoneda, Yukio.

In: Journal of Neuroscience Research, Vol. 88, No. 11, 15.08.2010, p. 2483-2493.

Research output: Contribution to journalArticle

Nakamichi, Noritaka ; Fukumori, Ryo ; Takarada, Takeshi ; Kambe, Yuki ; Yamamoto, Tomomi ; Matsushima, Nobuyuki ; Moriguchi, Nobuaki ; Yoneda, Yukio. / Preferential inhibition by antidiarrheic 2-methoxy-4-methylphenol of Ca2+ influx across acquired N-methyl-D-aspartate receptor channels composed of NR1/NR2B subunit assembly. In: Journal of Neuroscience Research. 2010 ; Vol. 88, No. 11. pp. 2483-2493.
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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 Ca2+ 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 Ca2+ 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 Ca2+ levels determined by Rhod-2, in addition to intracellular free Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ influx across NMDAR channels composed of NR1/NR2B subunits.",
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AU - Nakamichi, Noritaka

AU - Fukumori, Ryo

AU - Takarada, Takeshi

AU - Kambe, Yuki

AU - Yamamoto, Tomomi

AU - Matsushima, Nobuyuki

AU - Moriguchi, Nobuaki

AU - Yoneda, Yukio

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