DL-3-n-butylphthalide prevents neuronal cell death after focal cerebral ischemia in mice via the JNK pathway.
DL-3-n-Butylphthalide (NBP) has shown cytoprotective effects in animal models of stroke and has passed clinical trials as a therapeutic drug for stroke in China. Hence, as a potential clinical treatment for stroke, understanding the mechanism(s) of action of NBP is essential. This investigation aimed to delineate the cellular and molecular mechanism of NBP protection in neuronal cultures and in the ischemic brain. NBP (10 μM) attenuated serum deprivation-induced neuronal apoptosis and the production of reactive oxygen species (ROS) in cortical neuronal cultures. Adult male 129S2/sv mice were subjected to permanent occlusion of the middle cerebral artery (MCA). NBP (100 mg/kg, i.p.) administrated 2 hrs before or 1 hr after ischemia reduced ischemia-induced infarct formation, attenuated caspase-3 and caspase-9 activation in the ischemic brain. TUNEL-positive cells and mitochondrial release of cytochrome c and apoptosis-inducing factor (AIF) in the penumbra region were reduced by NBP. The proapoptotic signaling mediated by phospho-JNK and p38 expression was downregulated by NBP treatment in vitro and in vivo. It is suggested that NBP protects against ischemic damage via multiple mechanisms including mitochondria associated caspase-dependent and -independent apoptotic pathways. Previous and current studies and recent clinical trials encourage exploration of NBP as a neuroprotective drug for the treatment of ischemic stroke.
Li
Jimei
J
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
Li
Yin
Y
Ogle
Molly
M
Zhou
Xin
X
Song
Mingke
M
Song
Minke
M
Yu
Shan Ping
SP
Wei
Ling
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001572:Benzofurans / Q000494:pharmacology*; D015153:Blotting, Western; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D053453:Caspase 9 / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D020287:In Situ Nick-End Labeling; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D001572:Benzofurans; D018696:Neuroprotective Agents; C027125:3-n-butylphthalide; D048670:MAP Kinase Kinase 4; D053148:Caspase 3; D053453:Caspase 9
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