title: DL-3-n-butylphthalide prevents neuronal cell death after focal cerebral ischemia in mice via the JNK pathway.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Jimei
authors.initials: J
authors.lastname: Li
authors.forename: Yin
authors.initials: Y
authors.lastname: Li
authors.forename: Molly
authors.initials: M
authors.lastname: Ogle
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.forename: Mingke
authors.initials: M
authors.lastname: Song
authors.forename: Minke
authors.initials: M
authors.lastname: Song
authors.forename: Shan Ping
authors.initials: SP
authors.lastname: Yu
authors.forename: Ling
authors.initials: L
authors.lastname: Wei
mesh_terms: 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
chemical_list: D001572:Benzofurans; D018696:Neuroprotective Agents; C027125:3-n-butylphthalide; D048670:MAP Kinase Kinase 4; D053148:Caspase 3; D053453:Caspase 9
references.citation: Acta Pharmacol Sin. 2000 May;21(5):433-8
references.pmid: 11324442
references.citation: Science. 1997 Feb 21;275(5303):1132-6
references.pmid: 9027315
references.citation: J Biochem. 2004 Jun;135(6):653-6
references.pmid: 15213239
references.citation: J Neurosci. 2010 Jun 16;30(24):8180-9
references.pmid: 20554868
references.citation: J Biochem. 2004 Aug;136(2):123-6
references.pmid: 15496581
references.citation: Neurosci Lett. 2008 Mar 28;434(2):224-9
references.pmid: 18328624
references.citation: Yao Xue Xue Bao. 1998 Jul;33(7):486-92
references.pmid: 12016880
references.citation: Yao Xue Xue Bao. 1995 Dec;30(12):896-903
references.pmid: 8712015
references.citation: Chin Med Sci J. 1997 Jun;12(2):102-6
references.pmid: 11324493
references.citation: Neurobiol Dis. 2005 Jun-Jul;19(1-2):183-93
references.pmid: 15837573
references.citation: Biochim Biophys Acta. 2009 May;1787(5):402-13
references.pmid: 18848916
references.citation: Zhongguo Yao Li Xue Bao. 1999 Aug;20(8):696-700
references.pmid: 10678100
references.citation: Yao Xue Xue Bao. 1996;31(3):166-70
references.pmid: 9206264
references.citation: Exp Cell Res. 1993 Jan;204(1):54-60
references.pmid: 8416796
references.citation: Nature. 1999 Feb 4;397(6718):441-6
references.pmid: 9989411
references.citation: Acta Pharmacol Sin. 2003 Aug;24(8):796-804
references.pmid: 12904280
references.citation: Science. 1995 Nov 24;270(5240):1326-31
references.pmid: 7481820
references.citation: Science. 1997 Oct 3;278(5335):114-7
references.pmid: 9311914
references.citation: J Pharmacol Exp Ther. 2006 Jun;317(3):973-9
references.pmid: 16527903