Salvianolic acid A alleviates ischemic brain injury through the inhibition of inflammation and apoptosis and the promotion of neurogenesis in mice

Mei-Yin Chien; Cheng-Hung Chuang; Chang-Ming Chern; Kou-Tong Liou; Der-Zen Liu; Yu-Chang Hou; Yuh-Chiang Shen

doi:10.1016/j.freeradbiomed.2016.09.006

Salvianolic acid A alleviates ischemic brain injury through the inhibition of inflammation and apoptosis and the promotion of neurogenesis in mice

Free Radic Biol Med. 2016 Oct:99:508-519. doi: 10.1016/j.freeradbiomed.2016.09.006. Epub 2016 Sep 5.

Authors

Mei-Yin Chien¹, Cheng-Hung Chuang², Chang-Ming Chern³, Kou-Tong Liou⁴, Der-Zen Liu⁵, Yu-Chang Hou⁶, Yuh-Chiang Shen⁷

Affiliations

¹ School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan; Ko Da Pharmaceutical Co., Taoyuan, Taiwan.
² Department of Nutrition, Hungkuang University, Taichung, Taiwan.
³ 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.
⁴ Department of Combat Sports and Chinese Martial Arts, Chinese Culture University, Taipei, Taiwan.
⁵ 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.
⁶ Department of Chinese Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Taiwan; Department of Bioscience Technology, Chuan-Yuan Christian University, Taoyuan, Taiwan.
⁷ 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.

PMID: 27609227
DOI: 10.1016/j.freeradbiomed.2016.09.006

Abstract

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.

Keywords: Cdk5, doublecortin; Glycogen synthase kinase 3 (GSK3); Ischemic stroke; Salvianolic acid A (SalA); β-catenin.

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Antioxidants / pharmacology*
Apoptosis / drug effects
Blood-Brain Barrier / drug effects
Brain Ischemia / drug therapy*
Brain Ischemia / genetics
Brain Ischemia / mortality
Brain Ischemia / pathology
Brain-Derived Neurotrophic Factor / genetics
Brain-Derived Neurotrophic Factor / metabolism
Caffeic Acids / pharmacology*
Cyclin-Dependent Kinase 5 / genetics
Cyclin-Dependent Kinase 5 / metabolism
Disease Models, Animal
Doublecortin Domain Proteins
Doublecortin Protein
Drug Administration Schedule
Gene Expression Regulation
Glycogen Synthase Kinase 3 beta / genetics
Glycogen Synthase Kinase 3 beta / metabolism
Injections, Intravenous
Lactates / pharmacology*
Male
Mice
Mice, Inbred ICR
Microtubule-Associated Proteins / genetics
Microtubule-Associated Proteins / metabolism
Neurogenesis / drug effects
Neuropeptides / genetics
Neuropeptides / metabolism
Proto-Oncogene Proteins c-bcl-2 / genetics
Proto-Oncogene Proteins c-bcl-2 / metabolism
Reperfusion Injury / drug therapy*
Reperfusion Injury / genetics
Reperfusion Injury / mortality
Reperfusion Injury / pathology
Signal Transduction
Stroke / drug therapy*
Stroke / genetics
Stroke / mortality
Stroke / pathology
Survival Analysis
Transcription Factor RelA / genetics
Transcription Factor RelA / metabolism
beta Catenin / genetics
beta Catenin / metabolism

Substances

Anti-Inflammatory Agents, Non-Steroidal
Antioxidants
Brain-Derived Neurotrophic Factor
CTNNB1 protein, mouse
Caffeic Acids
Dcx protein, mouse
Doublecortin Domain Proteins
Doublecortin Protein
Lactates
Microtubule-Associated Proteins
Neuropeptides
Proto-Oncogene Proteins c-bcl-2
Rela protein, mouse
Transcription Factor RelA
beta Catenin
Bcl2 protein, mouse
salvianolic acid A
Cyclin-Dependent Kinase 5
Glycogen Synthase Kinase 3 beta
Gsk3b protein, mouse
Cdk5 protein, mouse