Baicalin inhibiting cerebral ischemia/hypoxia-induced neuronal apoptosis via MRTF-A-mediated transactivity.
Baicalin has been shown to provide the neuroprotective effect by alleviating cerebral ischemia injury. However, little's known about the underlying mechanism. Here, a cerebral artery occlusion (MACO)/reperfusion rat model and rat primary cortical neuron culture exposed to hydrogen peroxide (H2O2) were established to evaluate the effect of baicalin on ischemia-induced neuronal apoptosis. We found baicalin can significantly less neurological deficit and reduced infarct volume in vivo. And it efficiently inhibited neuronal apoptosis in vivo and vitro, which was especially characterized by the enhancing of transcription and expression of myeloid cell leukemia-1 (MCL-1) and B-cell lymphoma-2 (BCL-2) in a dose-dependent manner. Furthermore, Baicalin markedly increased myocardin-related transcription factor-A (MRTF-A) level either in ischemic hemisphere or in primary cortical neuron cultures, whiles the anti-apoptosis effect of baicalin was significantly inhibited by transfected with the small interfering RNA of MRTF-A (MRTF-A siRNA) in primary cortical neuron cultures. The luciferase assays also indicated baicalin enhanced the transactivity of MCL-1 and BCL-2 promoter by activating the key CArG box (CC [A/T] 6GG) element, which was reduced by MRTF-A siRNA, suggesting MRTF-A may participate the anti-apoptosis effect of baicalin, and MRTF-A was involved in the transcriptional activity of MCL-1 and BCL-2 that was induced by baicalin. LY294002 (phosphatidylinositol-3 kinase (PI3K) inhibitor) and PD98059 (extracellular signal regulates kinase-1/2 (ERK1/2) inhibitor) obviously reduced baicalin-induced MRTF-A expression and transactivity and expression of MCL-1 and BCL-2, which further abolished the anti-apoptotic effect of baicalin on neuronal apoptosis. Taken together, our data provided the evidence demonstrating the neuroprotective effect of baicalin partially due to MRTF-A-mediated transactivity and expression of MCL-1 and BCL-2 by triggering the CArG box, which might be controlled by the activation of PI3K and ERK1/2.
Department of Pharmacy, Yangtze River Shipping General Hospital, Wuhan, 430010 Hubei Province, China.
Wen-xia
WX
Zheng
Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, 430065 Hubei Province, China; Drug research base of cardiovascular and cerebral vascular, Wuhan University of Science and Technology, China.
Xiao-lu
XL
Cao
Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, 430065 Hubei Province, China; Drug research base of cardiovascular and cerebral vascular, Wuhan University of Science and Technology, China.
Feng
F
Wang
Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, 430065 Hubei Province, China; Drug research base of cardiovascular and cerebral vascular, Wuhan University of Science and Technology, China.
Jun
J
Wang
Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, 430065 Hubei Province, China; Drug research base of cardiovascular and cerebral vascular, Wuhan University of Science and Technology, China.
Ting-zi
TZ
Ying
Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, 430065 Hubei Province, China; Drug research base of cardiovascular and cerebral vascular, Wuhan University of Science and Technology, China.
Wan
W
Xiao
Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, 430065 Hubei Province, China; Drug research base of cardiovascular and cerebral vascular, Wuhan University of Science and Technology, China.
Ying
Y
Zhang
Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, 430065 Hubei Province, China.
Hong
H
Xing
Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, 430065 Hubei Province, China.
Wei
W
Dong
Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, 430065 Hubei Province, China.
Shi-qiang
SQ
Xu
Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, 430065 Hubei Province, China.
Zhen-li
ZL
Min
Department of Pharmacy, Yangtze River Shipping General Hospital, Wuhan, 430010 Hubei Province, China. Electronic address: wu_fangjian@163.com.
Fang-jian
FJ
Wu
Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, 430065 Hubei Province, China; Drug research base of cardiovascular and cerebral vascular, Wuhan University of Science and Technology, China. Electronic address: huxiaming@163.com.
Xia-min
XM
Hu
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology*; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000517:prevention & control*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D061251:Primary Cell Culture; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
D002867:Chromones; D005419:Flavonoids; C579093:Mcl1 protein, rat; D009025:Morpholines; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D018696:Neuroprotective Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D014157:Transcription Factors; C557977:myocardin-related transcription factor-A, rat; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C038044:baicalin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
BCL-2; Baicalin; ERK1/2; MCL-1; MRTF-A; Neuronal apoptosis; PI3K