Up-regulation of astroglial heme oxygenase-1 by a synthetic (S)-verbenone derivative LMT-335 ameliorates oxygen-glucose deprivation-evoked injury in cortical neurons

Chung Ju, Sumi Song, Minkyoung Kim, Yongseok Choi, Won-Ki Kim

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Excessive generation of free radicals is regarded as a major detrimental factor in cerebral ischemic insults. Neurons are particularly vulnerable to oxidative stress due to their limited anti-oxidant capacity. As an important source of antioxidants in the brain, astroglia are now thought to be attractive targets for pharmacological interventions to reduce neuronal oxidative stress in ischemic stroke. In the present study, we synthesized a novel antioxidant, the (1S)-(-)-verbenone derivative LMT-335, and investigated its anti-ischemic activities. In rat cortical neuronal/glial co-cultures, LMT-335 significantly reduced oxygen-glucose deprivation (OGD)/reoxygenation (R)-induced neuronal injury. Although it did not inhibit N-methyl d-aspartate-induced excitotoxicity, LMT-335 significantly reduced OGD/R-evoked intracellular oxidative stress. However, the oxygen radical absorbance capacity assay and 1,1-diphenyl-2-picrylhydrazyl assay showed that the free radical scavenging activities of LMT-335 were lower than those of trolox. Instead, LMT-335 significantly increased the astroglial expression of heme oxygenase-1 (HO-1), a well-known anti-oxidant stress protein, as evidenced by immunocytochemistry and immunoblot analyses. Moreover, a selective HO-1 inhibitor, tin protoporphyrin IX (SnPP), significantly blocked the anti-ischemic effect of LMT-335. The present findings indicate that LMT-335 exerts neuroprotective effects against OGD/R by up-regulation of HO-1 in astroglial cells. Our data suggest that astroglial HO-1 represents a potential therapeutic target for the treatment of ischemic stroke.

Original languageEnglish
Pages (from-to)484-489
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume431
Issue number3
DOIs
Publication statusPublished - 2013 Feb 15

Fingerprint

Heme Oxygenase-1
Neurons
Up-Regulation
Oxygen
Derivatives
Glucose
Wounds and Injuries
Oxidative stress
Oxidative Stress
Oxidants
Free Radicals
Assays
Antioxidants
Stroke
Scavenging
Neuroprotective Agents
Heat-Shock Proteins
Coculture Techniques
6,6-dimethyl-4-(4-methylstyryl)bicyclo(3.1.1)hept-3-en-2-one
verbenone

Keywords

  • Astroglia
  • Cerebral ischemia
  • Heme-oxygenase-1
  • LMT-335
  • Oxidative stress
  • Oxygen-glucose deprivation/re-oxygenation

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Molecular Biology

Cite this

@article{33ee50fd99aa46e7addefaaa776c4c2f,
title = "Up-regulation of astroglial heme oxygenase-1 by a synthetic (S)-verbenone derivative LMT-335 ameliorates oxygen-glucose deprivation-evoked injury in cortical neurons",
abstract = "Excessive generation of free radicals is regarded as a major detrimental factor in cerebral ischemic insults. Neurons are particularly vulnerable to oxidative stress due to their limited anti-oxidant capacity. As an important source of antioxidants in the brain, astroglia are now thought to be attractive targets for pharmacological interventions to reduce neuronal oxidative stress in ischemic stroke. In the present study, we synthesized a novel antioxidant, the (1S)-(-)-verbenone derivative LMT-335, and investigated its anti-ischemic activities. In rat cortical neuronal/glial co-cultures, LMT-335 significantly reduced oxygen-glucose deprivation (OGD)/reoxygenation (R)-induced neuronal injury. Although it did not inhibit N-methyl d-aspartate-induced excitotoxicity, LMT-335 significantly reduced OGD/R-evoked intracellular oxidative stress. However, the oxygen radical absorbance capacity assay and 1,1-diphenyl-2-picrylhydrazyl assay showed that the free radical scavenging activities of LMT-335 were lower than those of trolox. Instead, LMT-335 significantly increased the astroglial expression of heme oxygenase-1 (HO-1), a well-known anti-oxidant stress protein, as evidenced by immunocytochemistry and immunoblot analyses. Moreover, a selective HO-1 inhibitor, tin protoporphyrin IX (SnPP), significantly blocked the anti-ischemic effect of LMT-335. The present findings indicate that LMT-335 exerts neuroprotective effects against OGD/R by up-regulation of HO-1 in astroglial cells. Our data suggest that astroglial HO-1 represents a potential therapeutic target for the treatment of ischemic stroke.",
keywords = "Astroglia, Cerebral ischemia, Heme-oxygenase-1, LMT-335, Oxidative stress, Oxygen-glucose deprivation/re-oxygenation",
author = "Chung Ju and Sumi Song and Minkyoung Kim and Yongseok Choi and Won-Ki Kim",
year = "2013",
month = "2",
day = "15",
doi = "10.1016/j.bbrc.2013.01.033",
language = "English",
volume = "431",
pages = "484--489",
journal = "The BMJ",
issn = "0730-6512",
publisher = "Kluwer Academic Publishers",
number = "3",

}

TY - JOUR

T1 - Up-regulation of astroglial heme oxygenase-1 by a synthetic (S)-verbenone derivative LMT-335 ameliorates oxygen-glucose deprivation-evoked injury in cortical neurons

AU - Ju, Chung

AU - Song, Sumi

AU - Kim, Minkyoung

AU - Choi, Yongseok

AU - Kim, Won-Ki

PY - 2013/2/15

Y1 - 2013/2/15

N2 - Excessive generation of free radicals is regarded as a major detrimental factor in cerebral ischemic insults. Neurons are particularly vulnerable to oxidative stress due to their limited anti-oxidant capacity. As an important source of antioxidants in the brain, astroglia are now thought to be attractive targets for pharmacological interventions to reduce neuronal oxidative stress in ischemic stroke. In the present study, we synthesized a novel antioxidant, the (1S)-(-)-verbenone derivative LMT-335, and investigated its anti-ischemic activities. In rat cortical neuronal/glial co-cultures, LMT-335 significantly reduced oxygen-glucose deprivation (OGD)/reoxygenation (R)-induced neuronal injury. Although it did not inhibit N-methyl d-aspartate-induced excitotoxicity, LMT-335 significantly reduced OGD/R-evoked intracellular oxidative stress. However, the oxygen radical absorbance capacity assay and 1,1-diphenyl-2-picrylhydrazyl assay showed that the free radical scavenging activities of LMT-335 were lower than those of trolox. Instead, LMT-335 significantly increased the astroglial expression of heme oxygenase-1 (HO-1), a well-known anti-oxidant stress protein, as evidenced by immunocytochemistry and immunoblot analyses. Moreover, a selective HO-1 inhibitor, tin protoporphyrin IX (SnPP), significantly blocked the anti-ischemic effect of LMT-335. The present findings indicate that LMT-335 exerts neuroprotective effects against OGD/R by up-regulation of HO-1 in astroglial cells. Our data suggest that astroglial HO-1 represents a potential therapeutic target for the treatment of ischemic stroke.

AB - Excessive generation of free radicals is regarded as a major detrimental factor in cerebral ischemic insults. Neurons are particularly vulnerable to oxidative stress due to their limited anti-oxidant capacity. As an important source of antioxidants in the brain, astroglia are now thought to be attractive targets for pharmacological interventions to reduce neuronal oxidative stress in ischemic stroke. In the present study, we synthesized a novel antioxidant, the (1S)-(-)-verbenone derivative LMT-335, and investigated its anti-ischemic activities. In rat cortical neuronal/glial co-cultures, LMT-335 significantly reduced oxygen-glucose deprivation (OGD)/reoxygenation (R)-induced neuronal injury. Although it did not inhibit N-methyl d-aspartate-induced excitotoxicity, LMT-335 significantly reduced OGD/R-evoked intracellular oxidative stress. However, the oxygen radical absorbance capacity assay and 1,1-diphenyl-2-picrylhydrazyl assay showed that the free radical scavenging activities of LMT-335 were lower than those of trolox. Instead, LMT-335 significantly increased the astroglial expression of heme oxygenase-1 (HO-1), a well-known anti-oxidant stress protein, as evidenced by immunocytochemistry and immunoblot analyses. Moreover, a selective HO-1 inhibitor, tin protoporphyrin IX (SnPP), significantly blocked the anti-ischemic effect of LMT-335. The present findings indicate that LMT-335 exerts neuroprotective effects against OGD/R by up-regulation of HO-1 in astroglial cells. Our data suggest that astroglial HO-1 represents a potential therapeutic target for the treatment of ischemic stroke.

KW - Astroglia

KW - Cerebral ischemia

KW - Heme-oxygenase-1

KW - LMT-335

KW - Oxidative stress

KW - Oxygen-glucose deprivation/re-oxygenation

UR - http://www.scopus.com/inward/record.url?scp=84873736581&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84873736581&partnerID=8YFLogxK

U2 - 10.1016/j.bbrc.2013.01.033

DO - 10.1016/j.bbrc.2013.01.033

M3 - Article

VL - 431

SP - 484

EP - 489

JO - The BMJ

JF - The BMJ

SN - 0730-6512

IS - 3

ER -