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, trans-
hinokiresinol, 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 stereo-specific 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.