Exp Mol Med.  2010 Dec;42(12):811-822. 10.3858/emm.2010.42.12.084.

Baicalein protects HT22 murine hippocampal neuronal cells against endoplasmic reticulum stress-induced apoptosis through inhibition of reactive oxygen species production and CHOP induction

Affiliations
  • 1Department of Biochemistry and Molecular Biology, School of Medicine, Medical Science and Engineering Research Center for Bioreaction to Reactive Oxygen Species Biomedical Science Institute, Kyung Hee University, Seoul 130-701, Korea. iskang@khu.ac.kr
  • 2Department of Biochemistry, Gachon University of Medicine and Science, Incheon 406-799, Korea. iskang@khu.ac.kr

Abstract

Baicalein is one of the major flavonoids in Scutellaria baicalensis Georgi and possesses various effects, including cytoprotection and anti-inflammation. Because endoplasmic reticulum (ER) stress has been implicated in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and cerebral ischemia, we investigated the effects of baicalein on apoptotic death of HT22 mouse hippocampal neuronal cells induced by thapsigargin (TG) and brefeldin A (BFA), two representative ER stress inducers. Apoptosis, reactive oxygen species (ROS) production, and mitochondrial membrane potential (MMP) were measured by flow cytometry. Expression level and phosphorylation status of ER stress-associated proteins and activation and cleavage of apoptosis-associated proteins were analyzed by Western blot. Baicalein reduced TG- and BFA-induced apoptosis of HT22 cells and activation and cleavage of apoptosis-associated proteins, such as caspase-12 and -3 and poly(ADP-ribose) polymerase. Baicalein also reduced the TG- and BFA-induced expression of ER stress-associated proteins, including C/EBP homologous protein (CHOP) and glucose-regulated protein 78, the cleavage of X-box binding protein-1 and activating transcription factor 6alpha, and the phosphorylation of eukaryotic initiation factor-2alpha and mitogen-activated protein kinases, such as p38, JNK, and ERK. Knock-down of CHOP expression by siRNA transfection and specific inhibitors of p38 (SB203580), JNK (SP600125), and ERK (PD98059) as well as anti-oxidant (N-acetylcysteine) reduced TG- or BFA-induced cell death. Baicalein also reduced TG- and BFA-induced ROS accumulation and MMP reduction. Taken together, these results suggest that baicalein could protect HT22 neuronal cells against ER stress-induced apoptosis by reducing CHOP induction as well as ROS accumulation and mitochondrial damage.

Keyword

apoptosis; baicalein; brefeldin A; endoplasmic reticulum; reactive oxygen species; thapsigargin

MeSH Terms

Animals
*Apoptosis
Brefeldin A/pharmacology
Cell Line
Cytoprotection
DNA-Binding Proteins/metabolism
Endoplasmic Reticulum/drug effects/*physiology
Flavanones/*pharmacology
Heat-Shock Proteins/biosynthesis
Hippocampus/cytology
Membrane Potential, Mitochondrial/drug effects
Mice
Mitogen-Activated Protein Kinases/metabolism
Neurons/*drug effects/physiology
Reactive Oxygen Species/*metabolism
Signal Transduction/drug effects
Thapsigargin/pharmacology
Transcription Factor CHOP/*biosynthesis
Transcription Factors/metabolism
Unfolded Protein Response/drug effects
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