dl-3-n-Butylphthalide Prevents Neuronal Cell Death after Focal Cerebral Ischemia in Mice via the JNK Pathway

• Type of Material: Article
• Authors: Jimei Li, Medical University of South Carolina; Yin Li, Medical University of South Carolina; Molly Ogle, Emory University; Xin Zhou, Emory University; Minke Song, Emory University; Shan Ping Yu, Emory University; Ling Wei, Emory University
• Language: English
• Date: 2010-11-04
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2010 Elsevier B.V. All rights reserved
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.brainres.2010.08.061
• Title of Journal or Parent Work: Brain Research
• ISSN: 0006-8993
• Volume: 1359
• Start Page: 216
• End Page: 226
• Grant/Funding Information: This work was supported by American Heart Association EIA grant 0840110N and the NIH grant C06 RR015455 from the Extramural Research Facilities Program of the National Center for Research Resources.
• Keywords: MAP kinase; Apoptosis; AIF; Cytochrome C; Mitochondria; Caspase; Ischemic stroke; dl-3-n-butylphthalide
• Research Categories: Health Sciences, Pathology; Health Sciences, Medicine and Surgery; Biology, Neuroscience

Abstract

dl-3-n-Butylphthalide (NBP) has shown cytoprotective effects in animal models of stroke and has passed clinical trails 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 M) attenuated serum deprivation-induced neuronal apoptosis and the production of reactive oxygen species (ROS) in cortical neuronal cultures. Adult male 129 S2/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 pro-apoptotic signaling mediated by phospho-JNK and p38 expression was down-regulated 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.