Extension of ischemic therapeutic time window by a free radical scavenger, Edaravone, reperfused with tPA in rat brain

Wenri Zhang, Keiko Sato, Takeshi Hayashi, Nobuhiko Omori, Isao Nagano, Shinsuke Kato, Seikoh Horiuchi, Koji Abe

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

3-methyl-1-phenyl-2-pyrazolin-5-one (Edaravone) is a free radical scavenger. We tested the hypothesis that combination treatment of Edaravone and recombinant tissue plasminogen activator (tPA) extends the therapeutic time window. Male Wistar rats were subjected to 1.5-, 3.0- or 4.5-hour middle cerebral artery (MCA) occlusion (MCAO) by a nylon thread. Animals were randomly divided into four groups. The Sham group rats were operated without MCAO and drug injection. In the Vehicle-treated group the same volume of saline was given every 1.5 hours from just after MCAO to just before reperfusion. In the Vehicle+tPA-treated group saline injection was given as above and tPA (5 mg/kg, i.v.) was given once just after reperfusion. Edaravone+tPA-treated group: Edaravone(3 mg/kg, i. v.) was given every 1.5 hours instead of saline and tPA injection as above. Survival rate, infarct size and evidence of apoptosis and hemorrhage were examined in the animals. Combining administration of Edaravone+tPA significantly increased survival rate after 3 hours of transient MCAO, and reduced infarct volume after 1.5 hours of transient MCAO compared with the vehicle or vehicle+tPA groups. In Edaravone+tPA-treated group, the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL) and 4-hydroxynonenal (4-HNE) positive cells were reduced at 16 hours after 3 hours of transient MCAO, but not in advanced glycation end products (AGEs) and 8-hydroxy-2′deoxyguanosine (8-OHdG). Hemorrhage rate and the area decreased in the Edaravone+tPA-treated group. The combination therapy of Edaravone+tPA increased survival rate, and reduced the infarct volume and hemorrhage with reduction of lipid peroxidation. Therefore, Edaravone combination is expected to extend the therapeutic time window of tPA in the clinical situation.

Original languageEnglish
Pages (from-to)342-348
Number of pages7
JournalNeurological Research
Volume26
Issue number3
DOIs
Publication statusPublished - Apr 2004

Fingerprint

Free Radical Scavengers
Tissue Plasminogen Activator
Brain
Therapeutics
In Situ Nick-End Labeling
Hemorrhage
Injections
Reperfusion
phenylmethylpyrazolone
Advanced Glycosylation End Products
DNA Nucleotidylexotransferase
Middle Cerebral Artery Infarction
Nylons
Biotin
Lipid Peroxidation
Wistar Rats
Apoptosis

Keywords

  • Edaravone
  • Free radical scavenger
  • Stroke
  • Therapeutic time window
  • tPA

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

Cite this

Extension of ischemic therapeutic time window by a free radical scavenger, Edaravone, reperfused with tPA in rat brain. / Zhang, Wenri; Sato, Keiko; Hayashi, Takeshi; Omori, Nobuhiko; Nagano, Isao; Kato, Shinsuke; Horiuchi, Seikoh; Abe, Koji.

In: Neurological Research, Vol. 26, No. 3, 04.2004, p. 342-348.

Research output: Contribution to journalArticle

Zhang, Wenri ; Sato, Keiko ; Hayashi, Takeshi ; Omori, Nobuhiko ; Nagano, Isao ; Kato, Shinsuke ; Horiuchi, Seikoh ; Abe, Koji. / Extension of ischemic therapeutic time window by a free radical scavenger, Edaravone, reperfused with tPA in rat brain. In: Neurological Research. 2004 ; Vol. 26, No. 3. pp. 342-348.
@article{dcce2066c49146c1940339dc95f12a66,
title = "Extension of ischemic therapeutic time window by a free radical scavenger, Edaravone, reperfused with tPA in rat brain",
abstract = "3-methyl-1-phenyl-2-pyrazolin-5-one (Edaravone) is a free radical scavenger. We tested the hypothesis that combination treatment of Edaravone and recombinant tissue plasminogen activator (tPA) extends the therapeutic time window. Male Wistar rats were subjected to 1.5-, 3.0- or 4.5-hour middle cerebral artery (MCA) occlusion (MCAO) by a nylon thread. Animals were randomly divided into four groups. The Sham group rats were operated without MCAO and drug injection. In the Vehicle-treated group the same volume of saline was given every 1.5 hours from just after MCAO to just before reperfusion. In the Vehicle+tPA-treated group saline injection was given as above and tPA (5 mg/kg, i.v.) was given once just after reperfusion. Edaravone+tPA-treated group: Edaravone(3 mg/kg, i. v.) was given every 1.5 hours instead of saline and tPA injection as above. Survival rate, infarct size and evidence of apoptosis and hemorrhage were examined in the animals. Combining administration of Edaravone+tPA significantly increased survival rate after 3 hours of transient MCAO, and reduced infarct volume after 1.5 hours of transient MCAO compared with the vehicle or vehicle+tPA groups. In Edaravone+tPA-treated group, the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL) and 4-hydroxynonenal (4-HNE) positive cells were reduced at 16 hours after 3 hours of transient MCAO, but not in advanced glycation end products (AGEs) and 8-hydroxy-2′deoxyguanosine (8-OHdG). Hemorrhage rate and the area decreased in the Edaravone+tPA-treated group. The combination therapy of Edaravone+tPA increased survival rate, and reduced the infarct volume and hemorrhage with reduction of lipid peroxidation. Therefore, Edaravone combination is expected to extend the therapeutic time window of tPA in the clinical situation.",
keywords = "Edaravone, Free radical scavenger, Stroke, Therapeutic time window, tPA",
author = "Wenri Zhang and Keiko Sato and Takeshi Hayashi and Nobuhiko Omori and Isao Nagano and Shinsuke Kato and Seikoh Horiuchi and Koji Abe",
year = "2004",
month = "4",
doi = "10.1179/016164104225014058",
language = "English",
volume = "26",
pages = "342--348",
journal = "Neurological Research",
issn = "0161-6412",
publisher = "Maney Publishing",
number = "3",

}

TY - JOUR

T1 - Extension of ischemic therapeutic time window by a free radical scavenger, Edaravone, reperfused with tPA in rat brain

AU - Zhang, Wenri

AU - Sato, Keiko

AU - Hayashi, Takeshi

AU - Omori, Nobuhiko

AU - Nagano, Isao

AU - Kato, Shinsuke

AU - Horiuchi, Seikoh

AU - Abe, Koji

PY - 2004/4

Y1 - 2004/4

N2 - 3-methyl-1-phenyl-2-pyrazolin-5-one (Edaravone) is a free radical scavenger. We tested the hypothesis that combination treatment of Edaravone and recombinant tissue plasminogen activator (tPA) extends the therapeutic time window. Male Wistar rats were subjected to 1.5-, 3.0- or 4.5-hour middle cerebral artery (MCA) occlusion (MCAO) by a nylon thread. Animals were randomly divided into four groups. The Sham group rats were operated without MCAO and drug injection. In the Vehicle-treated group the same volume of saline was given every 1.5 hours from just after MCAO to just before reperfusion. In the Vehicle+tPA-treated group saline injection was given as above and tPA (5 mg/kg, i.v.) was given once just after reperfusion. Edaravone+tPA-treated group: Edaravone(3 mg/kg, i. v.) was given every 1.5 hours instead of saline and tPA injection as above. Survival rate, infarct size and evidence of apoptosis and hemorrhage were examined in the animals. Combining administration of Edaravone+tPA significantly increased survival rate after 3 hours of transient MCAO, and reduced infarct volume after 1.5 hours of transient MCAO compared with the vehicle or vehicle+tPA groups. In Edaravone+tPA-treated group, the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL) and 4-hydroxynonenal (4-HNE) positive cells were reduced at 16 hours after 3 hours of transient MCAO, but not in advanced glycation end products (AGEs) and 8-hydroxy-2′deoxyguanosine (8-OHdG). Hemorrhage rate and the area decreased in the Edaravone+tPA-treated group. The combination therapy of Edaravone+tPA increased survival rate, and reduced the infarct volume and hemorrhage with reduction of lipid peroxidation. Therefore, Edaravone combination is expected to extend the therapeutic time window of tPA in the clinical situation.

AB - 3-methyl-1-phenyl-2-pyrazolin-5-one (Edaravone) is a free radical scavenger. We tested the hypothesis that combination treatment of Edaravone and recombinant tissue plasminogen activator (tPA) extends the therapeutic time window. Male Wistar rats were subjected to 1.5-, 3.0- or 4.5-hour middle cerebral artery (MCA) occlusion (MCAO) by a nylon thread. Animals were randomly divided into four groups. The Sham group rats were operated without MCAO and drug injection. In the Vehicle-treated group the same volume of saline was given every 1.5 hours from just after MCAO to just before reperfusion. In the Vehicle+tPA-treated group saline injection was given as above and tPA (5 mg/kg, i.v.) was given once just after reperfusion. Edaravone+tPA-treated group: Edaravone(3 mg/kg, i. v.) was given every 1.5 hours instead of saline and tPA injection as above. Survival rate, infarct size and evidence of apoptosis and hemorrhage were examined in the animals. Combining administration of Edaravone+tPA significantly increased survival rate after 3 hours of transient MCAO, and reduced infarct volume after 1.5 hours of transient MCAO compared with the vehicle or vehicle+tPA groups. In Edaravone+tPA-treated group, the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL) and 4-hydroxynonenal (4-HNE) positive cells were reduced at 16 hours after 3 hours of transient MCAO, but not in advanced glycation end products (AGEs) and 8-hydroxy-2′deoxyguanosine (8-OHdG). Hemorrhage rate and the area decreased in the Edaravone+tPA-treated group. The combination therapy of Edaravone+tPA increased survival rate, and reduced the infarct volume and hemorrhage with reduction of lipid peroxidation. Therefore, Edaravone combination is expected to extend the therapeutic time window of tPA in the clinical situation.

KW - Edaravone

KW - Free radical scavenger

KW - Stroke

KW - Therapeutic time window

KW - tPA

UR - http://www.scopus.com/inward/record.url?scp=2442462438&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=2442462438&partnerID=8YFLogxK

U2 - 10.1179/016164104225014058

DO - 10.1179/016164104225014058

M3 - Article

C2 - 15142331

AN - SCOPUS:2442462438

VL - 26

SP - 342

EP - 348

JO - Neurological Research

JF - Neurological Research

SN - 0161-6412

IS - 3

ER -