Salvianolic acid A alleviates ischemic brain injury through the inhibition of inflammation and apoptosis and the promotion of neurogenesis in mice.
Salvianolic acid A (SalA), a chemical type of caffeic acid trimer, has drawn great attention for its potent bioactivities against ischemia-induced injury both in vitro and in vivo. In this study, we evaluated SalA's protective effects against acute ischemic stroke by inducing middle cerebral artery occlusion/reperfusion (MCAO) injuries in mice. Treatment of the mice with SalA (50 and 100μg/kg, i.v.) at 2h after MCAO enhanced their survival rate, improved their moving activity, and ameliorated the severity of brain infarction and apoptosis seen in the mice by diminishing pathological changes such as the extensive breakdown of the blood-brain barrier (BBB), nitrosative stress, and the activation of an inflammatory transcriptional factor p65 nuclear factor-kappa B (NF-κB) and a pro-apoptotic kinase p25/Cdk5. SalA also intensively limited cortical infarction and promoted the expression of neurogenesis protein near the peri-infarct cortex and subgranular zone of the hippocampal dentate gyrus by compromising the activation of GSK3β and p25/Cdk5, which in turn upregulated β-catenin, doublecortin (DCX), and Bcl-2, most possibly through the activation of PI3K/Akt signaling via the upregulation of brain-derived neurotrophic factor. We conclude that SalA blocks inflammatory responses by impairing NF-κB signaling, thereby limiting inflammation/nitrosative stress and preserving the integrity of the BBB; SalA also concomitantly promotes neurogenesis-related protein expression by compromising GSK3β/Cdk5 activity to enhance the expression levels of β-catenin/DCX and Bcl-2 for neuroprotection.
School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan; Ko Da Pharmaceutical Co., Taoyuan, Taiwan.
Mei-Yin
MY
Chien
Department of Nutrition, Hungkuang University, Taichung, Taiwan.
Cheng-Hung
CH
Chuang
Division of Neurovascular Disease, Neurological Institute, Taipei Veterans General Hospital & Taipei Municipal Gan-Dau Hospital, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Chang-Ming
CM
Chern
Department of Combat Sports and Chinese Martial Arts, Chinese Culture University, Taipei, Taiwan.
Kou-Tong
KT
Liou
Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan; Center for General Education, Hsuan Chuang University, Hsinchu, Taiwan. Electronic address: tonyliu@tmu.edu.tw.
Der-Zen
DZ
Liu
Department of Chinese Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Taiwan; Department of Bioscience Technology, Chuan-Yuan Christian University, Taoyuan, Taiwan.
Yu-Chang
YC
Hou
National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan; Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, Taiwan; National Taipei University of Nursing and Health Science, Taipei, Taiwan. Electronic address: yuhcs@nricm.edu.tw.
Yuh-Chiang
YC
Shen
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002109:Caffeic Acids / Q000494:pharmacology*; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism; D007275:Injections, Intravenous; D007773:Lactates / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D015398:Signal Transduction; D020521:Stroke / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D019208:Brain-Derived Neurotrophic Factor; C495267:CTNNB1 protein, mouse; D002109:Caffeic Acids; C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D007773:Lactates; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D019253:Proto-Oncogene Proteins c-bcl-2; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D051176:beta Catenin; C052617:Bcl2 protein, mouse; C066201:salvianolic acid A; D051360:Cyclin-Dependent Kinase 5; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C495906:Cdk5 protein, mouse
Cdk5, doublecortin; Glycogen synthase kinase 3 (GSK3); Ischemic stroke; Salvianolic acid A (SalA); β-catenin