Effects of blockade of voltage-sensitive Ca2+/Na+ channels by a novel phenylpyrimidine derivative, NS-7, on CREB phosphorylation in focal cerebral ischemia in the rat

Kortaro Tanaka, Shigeru Nogawa, Eiichiro Nagata, Shigeaki Suzuki, Tomohisa Dembo, Arifumi Kosakai, Yasuo Fukuuchi

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

NS-7 is a novel blocker of voltage-sensitive Ca2+ and Na+ channels, and it significantly reduces infarct size after occlusion of the middle cerebral artery. Persistent activation of cyclic AMP response element binding protein (CREB), which can be induced by increase in intracellular Ca2+ concentrations or other second messengers, has recently been found to be closely associated with neuronal survival in cerebral ischemia. The present study was therefore undertaken to evaluate the neuroprotective effects of NS-7 by analyzing changes in CREB phosphorylation in a focal cerebral ischemia model. CREB phosphorylation in the brain of rats was investigated immunohistochemically at 3.5-48-h recirculation after 1.5-h occlusion of the middle cerebral artery. NS-7 (1 mg/kg; NS-7 group) or saline (saline group) was intravenously injected 5 min after the start of recirculation. The NS-7 group showed significantly milder activation of CREB phosphorylation in various cortical regions after 3.5 h of recirculation than the saline group. The inner border zone of ischemia in the NS-7 group subsequently exhibited a moderate, but persistent, increase in number of phosphorylated CREB-positive neurons with no apparent histological damage. By contrast, the saline group displayed a marked, but only transient, increase in number of immunopositive neurons in this border zone after 3.5 h of recirculation, and this was followed by clear suppression of CREB phosphorylation and subsequent loss of normal neurons. These findings suggest that: (1) the marked enhancement of CREB phosphorylation in the acute post-ischemic phase may be triggered largely by an influx of calcium ions as a result of activation of the voltage-sensitive Ca2+ and Na+ channels; and that (2) the neuroprotective effects of NS-7 may be accompanied by persistent activation of CREB phosphorylation in the inner border zone of ischemia. Copyright (C) 2000 Elsevier Science B.V.

Original languageEnglish
Pages (from-to)83-93
Number of pages11
JournalBrain Research
Volume873
Issue number1
DOIs
Publication statusPublished - 2000 Aug 4

Fingerprint

Cyclic AMP Response Element-Binding Protein
Brain Ischemia
Phosphorylation
Middle Cerebral Artery Infarction
Neuroprotective Agents
Neurons
Ischemia
4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy)pyrimidine hydrochloride
Second Messenger Systems
Ions
Calcium
Brain

Keywords

  • Ca channel
  • Cerebral ischemia
  • CREB
  • Cyclic AMP response element binding protein
  • Na channel
  • Phosphorylation

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Effects of blockade of voltage-sensitive Ca2+/Na+ channels by a novel phenylpyrimidine derivative, NS-7, on CREB phosphorylation in focal cerebral ischemia in the rat. / Tanaka, Kortaro; Nogawa, Shigeru; Nagata, Eiichiro; Suzuki, Shigeaki; Dembo, Tomohisa; Kosakai, Arifumi; Fukuuchi, Yasuo.

In: Brain Research, Vol. 873, No. 1, 04.08.2000, p. 83-93.

Research output: Contribution to journalArticle

Tanaka, Kortaro ; Nogawa, Shigeru ; Nagata, Eiichiro ; Suzuki, Shigeaki ; Dembo, Tomohisa ; Kosakai, Arifumi ; Fukuuchi, Yasuo. / Effects of blockade of voltage-sensitive Ca2+/Na+ channels by a novel phenylpyrimidine derivative, NS-7, on CREB phosphorylation in focal cerebral ischemia in the rat. In: Brain Research. 2000 ; Vol. 873, No. 1. pp. 83-93.
@article{89da9084a6d14f15908e663354f0dcc8,
title = "Effects of blockade of voltage-sensitive Ca2+/Na+ channels by a novel phenylpyrimidine derivative, NS-7, on CREB phosphorylation in focal cerebral ischemia in the rat",
abstract = "NS-7 is a novel blocker of voltage-sensitive Ca2+ and Na+ channels, and it significantly reduces infarct size after occlusion of the middle cerebral artery. Persistent activation of cyclic AMP response element binding protein (CREB), which can be induced by increase in intracellular Ca2+ concentrations or other second messengers, has recently been found to be closely associated with neuronal survival in cerebral ischemia. The present study was therefore undertaken to evaluate the neuroprotective effects of NS-7 by analyzing changes in CREB phosphorylation in a focal cerebral ischemia model. CREB phosphorylation in the brain of rats was investigated immunohistochemically at 3.5-48-h recirculation after 1.5-h occlusion of the middle cerebral artery. NS-7 (1 mg/kg; NS-7 group) or saline (saline group) was intravenously injected 5 min after the start of recirculation. The NS-7 group showed significantly milder activation of CREB phosphorylation in various cortical regions after 3.5 h of recirculation than the saline group. The inner border zone of ischemia in the NS-7 group subsequently exhibited a moderate, but persistent, increase in number of phosphorylated CREB-positive neurons with no apparent histological damage. By contrast, the saline group displayed a marked, but only transient, increase in number of immunopositive neurons in this border zone after 3.5 h of recirculation, and this was followed by clear suppression of CREB phosphorylation and subsequent loss of normal neurons. These findings suggest that: (1) the marked enhancement of CREB phosphorylation in the acute post-ischemic phase may be triggered largely by an influx of calcium ions as a result of activation of the voltage-sensitive Ca2+ and Na+ channels; and that (2) the neuroprotective effects of NS-7 may be accompanied by persistent activation of CREB phosphorylation in the inner border zone of ischemia. Copyright (C) 2000 Elsevier Science B.V.",
keywords = "Ca channel, Cerebral ischemia, CREB, Cyclic AMP response element binding protein, Na channel, Phosphorylation",
author = "Kortaro Tanaka and Shigeru Nogawa and Eiichiro Nagata and Shigeaki Suzuki and Tomohisa Dembo and Arifumi Kosakai and Yasuo Fukuuchi",
year = "2000",
month = "8",
day = "4",
doi = "10.1016/S0006-8993(00)02512-9",
language = "English",
volume = "873",
pages = "83--93",
journal = "Brain Research",
issn = "0006-8993",
publisher = "Elsevier",
number = "1",

}

TY - JOUR

T1 - Effects of blockade of voltage-sensitive Ca2+/Na+ channels by a novel phenylpyrimidine derivative, NS-7, on CREB phosphorylation in focal cerebral ischemia in the rat

AU - Tanaka, Kortaro

AU - Nogawa, Shigeru

AU - Nagata, Eiichiro

AU - Suzuki, Shigeaki

AU - Dembo, Tomohisa

AU - Kosakai, Arifumi

AU - Fukuuchi, Yasuo

PY - 2000/8/4

Y1 - 2000/8/4

N2 - NS-7 is a novel blocker of voltage-sensitive Ca2+ and Na+ channels, and it significantly reduces infarct size after occlusion of the middle cerebral artery. Persistent activation of cyclic AMP response element binding protein (CREB), which can be induced by increase in intracellular Ca2+ concentrations or other second messengers, has recently been found to be closely associated with neuronal survival in cerebral ischemia. The present study was therefore undertaken to evaluate the neuroprotective effects of NS-7 by analyzing changes in CREB phosphorylation in a focal cerebral ischemia model. CREB phosphorylation in the brain of rats was investigated immunohistochemically at 3.5-48-h recirculation after 1.5-h occlusion of the middle cerebral artery. NS-7 (1 mg/kg; NS-7 group) or saline (saline group) was intravenously injected 5 min after the start of recirculation. The NS-7 group showed significantly milder activation of CREB phosphorylation in various cortical regions after 3.5 h of recirculation than the saline group. The inner border zone of ischemia in the NS-7 group subsequently exhibited a moderate, but persistent, increase in number of phosphorylated CREB-positive neurons with no apparent histological damage. By contrast, the saline group displayed a marked, but only transient, increase in number of immunopositive neurons in this border zone after 3.5 h of recirculation, and this was followed by clear suppression of CREB phosphorylation and subsequent loss of normal neurons. These findings suggest that: (1) the marked enhancement of CREB phosphorylation in the acute post-ischemic phase may be triggered largely by an influx of calcium ions as a result of activation of the voltage-sensitive Ca2+ and Na+ channels; and that (2) the neuroprotective effects of NS-7 may be accompanied by persistent activation of CREB phosphorylation in the inner border zone of ischemia. Copyright (C) 2000 Elsevier Science B.V.

AB - NS-7 is a novel blocker of voltage-sensitive Ca2+ and Na+ channels, and it significantly reduces infarct size after occlusion of the middle cerebral artery. Persistent activation of cyclic AMP response element binding protein (CREB), which can be induced by increase in intracellular Ca2+ concentrations or other second messengers, has recently been found to be closely associated with neuronal survival in cerebral ischemia. The present study was therefore undertaken to evaluate the neuroprotective effects of NS-7 by analyzing changes in CREB phosphorylation in a focal cerebral ischemia model. CREB phosphorylation in the brain of rats was investigated immunohistochemically at 3.5-48-h recirculation after 1.5-h occlusion of the middle cerebral artery. NS-7 (1 mg/kg; NS-7 group) or saline (saline group) was intravenously injected 5 min after the start of recirculation. The NS-7 group showed significantly milder activation of CREB phosphorylation in various cortical regions after 3.5 h of recirculation than the saline group. The inner border zone of ischemia in the NS-7 group subsequently exhibited a moderate, but persistent, increase in number of phosphorylated CREB-positive neurons with no apparent histological damage. By contrast, the saline group displayed a marked, but only transient, increase in number of immunopositive neurons in this border zone after 3.5 h of recirculation, and this was followed by clear suppression of CREB phosphorylation and subsequent loss of normal neurons. These findings suggest that: (1) the marked enhancement of CREB phosphorylation in the acute post-ischemic phase may be triggered largely by an influx of calcium ions as a result of activation of the voltage-sensitive Ca2+ and Na+ channels; and that (2) the neuroprotective effects of NS-7 may be accompanied by persistent activation of CREB phosphorylation in the inner border zone of ischemia. Copyright (C) 2000 Elsevier Science B.V.

KW - Ca channel

KW - Cerebral ischemia

KW - CREB

KW - Cyclic AMP response element binding protein

KW - Na channel

KW - Phosphorylation

UR - http://www.scopus.com/inward/record.url?scp=0034604785&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034604785&partnerID=8YFLogxK

U2 - 10.1016/S0006-8993(00)02512-9

DO - 10.1016/S0006-8993(00)02512-9

M3 - Article

VL - 873

SP - 83

EP - 93

JO - Brain Research

JF - Brain Research

SN - 0006-8993

IS - 1

ER -