Differential anti-ischemic efficacy and therapeutic time window of trans- and cis-hinokiresinols: Stereo-specific antioxidant and anti-inflammatory activities

Chung Ju, Sunyoung Hwang, Geum Sil Cho, Gajulapati Kondaji, Sumi Song, Paul L. Prather, Yongseok Choi, Won-Ki Kim

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

During cerebral ischemia, neurons are injured by various mechanisms including excitotoxicity, oxidative stress, and inflammatory responses. Thus, pharmacological manipulation of multiple cytotoxic pathways has been pursued for the treatment of ischemic injury. Cis-hinokiresinol, a naturally occurring phenylpropanoid, was previously reported to possess anti-oxidant, anti-inflammatory and estrogen-like activities. In the present study, we investigated anti-ischemic effects of trans- and cis-hinokiresinols using in vitro as well as in vivo experimental models. The ORAC and DPPH assays showed that two isomers had similar free radical scavenging activities. However, only trans-hinokiresinol significantly decreased neuronal injury in cultured cortical neurons exposed to oxygen-glucose deprivation (75 min) followed by re-oxygenation (9 h). The differential neuroprotective effect could be due to the stereo-specific augmentation of Cu/Zn-SOD activity by trans-hinokiresinol, when compared with cis-hinokiresinol. Similarly, in rats subjected to transient middle cerebral artery occlusion (1.5 h) followed by 24-h reperfusion, pre-ischemic treatment with trans-hinokiresinol, but not with cis-isomer, reduced cerebral infarct volume. Interestingly, however, post-ischemic treatment with both hinokiresinols (2 and 7 h after onset of ischemia) significantly reduced cerebral infarct. When administered after onset of ischemia, transhinokiresinol, but not its cis-isomer reduced nitrotyrosine immunoreactivity in ischemic regions. In contrast, both hinokiresinols suppressed neutrophil infiltration and IL-1β release to a similar extent. The observed differential anti-oxidant, but comparable anti-inflammatory, activities may explain the stereospecific anti-ischemic activities and different therapeutic time windows of the hinokiresinols examined. More detailed delineation of the anti-ischemic mechanism(s) of hinokiresinols may provide a better strategy for development of efficacious regimens for cerebral ischemic stroke.

Original languageEnglish
Pages (from-to)465-475
Number of pages11
JournalNeuropharmacology
Volume67
DOIs
Publication statusPublished - 2013 Apr 1

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Anti-Inflammatory Agents
Antioxidants
Oxidants
Therapeutics
Ischemia
Neurons
Neutrophil Infiltration
Middle Cerebral Artery Infarction
Wounds and Injuries
Neuroprotective Agents
hinokiresinol
nyasol
Brain Ischemia
Interleukin-1
Reperfusion
Free Radicals
Estrogens
Oxidative Stress
Theoretical Models
Stroke

Keywords

  • Anti-inflammation
  • Antioxidant
  • Hinokiresinol
  • Middle cerebral artery occlusion
  • Oxygen-glucose deprivation
  • Stereo-specificity
  • Therapeutic window

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

Differential anti-ischemic efficacy and therapeutic time window of trans- and cis-hinokiresinols : Stereo-specific antioxidant and anti-inflammatory activities. / Ju, Chung; Hwang, Sunyoung; Cho, Geum Sil; Kondaji, Gajulapati; Song, Sumi; Prather, Paul L.; Choi, Yongseok; Kim, Won-Ki.

In: Neuropharmacology, Vol. 67, 01.04.2013, p. 465-475.

Research output: Contribution to journalArticle

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AB - During cerebral ischemia, neurons are injured by various mechanisms including excitotoxicity, oxidative stress, and inflammatory responses. Thus, pharmacological manipulation of multiple cytotoxic pathways has been pursued for the treatment of ischemic injury. Cis-hinokiresinol, a naturally occurring phenylpropanoid, was previously reported to possess anti-oxidant, anti-inflammatory and estrogen-like activities. In the present study, we investigated anti-ischemic effects of trans- and cis-hinokiresinols using in vitro as well as in vivo experimental models. The ORAC and DPPH assays showed that two isomers had similar free radical scavenging activities. However, only trans-hinokiresinol significantly decreased neuronal injury in cultured cortical neurons exposed to oxygen-glucose deprivation (75 min) followed by re-oxygenation (9 h). The differential neuroprotective effect could be due to the stereo-specific augmentation of Cu/Zn-SOD activity by trans-hinokiresinol, when compared with cis-hinokiresinol. Similarly, in rats subjected to transient middle cerebral artery occlusion (1.5 h) followed by 24-h reperfusion, pre-ischemic treatment with trans-hinokiresinol, but not with cis-isomer, reduced cerebral infarct volume. Interestingly, however, post-ischemic treatment with both hinokiresinols (2 and 7 h after onset of ischemia) significantly reduced cerebral infarct. When administered after onset of ischemia, transhinokiresinol, but not its cis-isomer reduced nitrotyrosine immunoreactivity in ischemic regions. In contrast, both hinokiresinols suppressed neutrophil infiltration and IL-1β release to a similar extent. The observed differential anti-oxidant, but comparable anti-inflammatory, activities may explain the stereospecific anti-ischemic activities and different therapeutic time windows of the hinokiresinols examined. More detailed delineation of the anti-ischemic mechanism(s) of hinokiresinols may provide a better strategy for development of efficacious regimens for cerebral ischemic stroke.

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