Neuroprotective effects of PMC, a potent α-tocopherol derivative, in brain ischemia-reperfusion: Reduced neutrophil activation and anti-oxidant actions

George Hsiao, Jie Jen Lee, Yi Cheng Chen, Jiing Harn Lin, Ming Yi Shen, Kuang Hung Lin, Duen Suey Chou, Joen Rong Sheu

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

2,2,5,7,8-Pentamethyl-6-hydroxychromane (PMC) is the most potent analogue of α-tocopherol for anti-oxidation. It is more hydrophilic than other α-tocopherol derivatives and has potent free radical-scavenging activity. In the present study, PMC significantly attenuated middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia in rats. Administration of PMC at 20 mg/kg, showed marked reductions in infarct size compared with that of control rats. MCAO-induced focal cerebral ischemia was associated with increases in HIF-1α, active caspase-3, iNOS, and nitrotyrosine expressions in ischemic regions. These expressions were markedly inhibited by treatment with PMC (20 mg/kg). In addition, PMC (4-12 μM) inhibited respiratory bursts in human neutrophils stimulated by fMLP (800 nM) and PMA (320 nM). Furthermore, PMC (6, 12, and 60 μM) also significantly inhibited neutrophil migration stimulated by leukotriene B4 (160 nM). An electron spin resonance (ESR) method was conducted on the scavenging activity of PMC on the free radicals formed. PMC (12 μM) greatly reduced the ESR signal intensities of superoxide anion, hydroxyl radical, and methyl radical formation. In conclusion, we demonstrate a potent neuroprotective effect of PMC on MCAO-induced focal cerebral ischemia in vivo. This effect may be mediated, at least in part, by inhibition of free radical formation, followed by inhibition of HIF-1α activation, apoptosis formation (active caspase-3), neutrophil activation, and inflammatory responses (i.e., iNOS and nitrotyrosine expressions), resulting in a reduction in the infarct volume in ischemia-reperfusion brain injury. Thus, PMC treatment may represent a novel approach to lowering the risk or improving function in ischemia-reperfusion brain injury-related disorders.

Original languageEnglish
Pages (from-to)682-693
Number of pages12
JournalBiochemical Pharmacology
Volume73
Issue number5
DOIs
Publication statusPublished - Mar 1 2007

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Neutrophil Activation
Tocopherols
Middle Cerebral Artery Infarction
Neuroprotective Agents
Brain Ischemia
Oxidants
Reperfusion
Free Radicals
Brain
Chemical activation
Scavenging
Electron Spin Resonance Spectroscopy
Reperfusion Injury
Derivatives
Caspase 3
Brain Injuries
Paramagnetic resonance
Neutrophils
Rat control
Leukotriene B4

Keywords

  • Caspase-3
  • Free radical-scavenger
  • HIF-1α
  • iNOS
  • MCAO
  • PMC

ASJC Scopus subject areas

  • Pharmacology

Cite this

Neuroprotective effects of PMC, a potent α-tocopherol derivative, in brain ischemia-reperfusion : Reduced neutrophil activation and anti-oxidant actions. / Hsiao, George; Lee, Jie Jen; Chen, Yi Cheng; Lin, Jiing Harn; Shen, Ming Yi; Lin, Kuang Hung; Chou, Duen Suey; Sheu, Joen Rong.

In: Biochemical Pharmacology, Vol. 73, No. 5, 01.03.2007, p. 682-693.

Research output: Contribution to journalArticle

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abstract = "2,2,5,7,8-Pentamethyl-6-hydroxychromane (PMC) is the most potent analogue of α-tocopherol for anti-oxidation. It is more hydrophilic than other α-tocopherol derivatives and has potent free radical-scavenging activity. In the present study, PMC significantly attenuated middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia in rats. Administration of PMC at 20 mg/kg, showed marked reductions in infarct size compared with that of control rats. MCAO-induced focal cerebral ischemia was associated with increases in HIF-1α, active caspase-3, iNOS, and nitrotyrosine expressions in ischemic regions. These expressions were markedly inhibited by treatment with PMC (20 mg/kg). In addition, PMC (4-12 μM) inhibited respiratory bursts in human neutrophils stimulated by fMLP (800 nM) and PMA (320 nM). Furthermore, PMC (6, 12, and 60 μM) also significantly inhibited neutrophil migration stimulated by leukotriene B4 (160 nM). An electron spin resonance (ESR) method was conducted on the scavenging activity of PMC on the free radicals formed. PMC (12 μM) greatly reduced the ESR signal intensities of superoxide anion, hydroxyl radical, and methyl radical formation. In conclusion, we demonstrate a potent neuroprotective effect of PMC on MCAO-induced focal cerebral ischemia in vivo. This effect may be mediated, at least in part, by inhibition of free radical formation, followed by inhibition of HIF-1α activation, apoptosis formation (active caspase-3), neutrophil activation, and inflammatory responses (i.e., iNOS and nitrotyrosine expressions), resulting in a reduction in the infarct volume in ischemia-reperfusion brain injury. Thus, PMC treatment may represent a novel approach to lowering the risk or improving function in ischemia-reperfusion brain injury-related disorders.",
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T1 - Neuroprotective effects of PMC, a potent α-tocopherol derivative, in brain ischemia-reperfusion

T2 - Reduced neutrophil activation and anti-oxidant actions

AU - Hsiao, George

AU - Lee, Jie Jen

AU - Chen, Yi Cheng

AU - Lin, Jiing Harn

AU - Shen, Ming Yi

AU - Lin, Kuang Hung

AU - Chou, Duen Suey

AU - Sheu, Joen Rong

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AB - 2,2,5,7,8-Pentamethyl-6-hydroxychromane (PMC) is the most potent analogue of α-tocopherol for anti-oxidation. It is more hydrophilic than other α-tocopherol derivatives and has potent free radical-scavenging activity. In the present study, PMC significantly attenuated middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia in rats. Administration of PMC at 20 mg/kg, showed marked reductions in infarct size compared with that of control rats. MCAO-induced focal cerebral ischemia was associated with increases in HIF-1α, active caspase-3, iNOS, and nitrotyrosine expressions in ischemic regions. These expressions were markedly inhibited by treatment with PMC (20 mg/kg). In addition, PMC (4-12 μM) inhibited respiratory bursts in human neutrophils stimulated by fMLP (800 nM) and PMA (320 nM). Furthermore, PMC (6, 12, and 60 μM) also significantly inhibited neutrophil migration stimulated by leukotriene B4 (160 nM). An electron spin resonance (ESR) method was conducted on the scavenging activity of PMC on the free radicals formed. PMC (12 μM) greatly reduced the ESR signal intensities of superoxide anion, hydroxyl radical, and methyl radical formation. In conclusion, we demonstrate a potent neuroprotective effect of PMC on MCAO-induced focal cerebral ischemia in vivo. This effect may be mediated, at least in part, by inhibition of free radical formation, followed by inhibition of HIF-1α activation, apoptosis formation (active caspase-3), neutrophil activation, and inflammatory responses (i.e., iNOS and nitrotyrosine expressions), resulting in a reduction in the infarct volume in ischemia-reperfusion brain injury. Thus, PMC treatment may represent a novel approach to lowering the risk or improving function in ischemia-reperfusion brain injury-related disorders.

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