Chrysophanol inhibits endoplasmic reticulum stress in cerebral ischemia and reperfusion mice.

Abstract

Endoplasmic reticulum (ER) stress plays a critical role in mediating ischemia/reperfusion (I/R) damage in the brain. Our previous study showed that Chrysophanol (CHR) alleviated cerebral ischemic injury in mice and nuclear factor-κB (NF-κB) involved in its neuroprotective effect, but the precise mechanism remains not fully understood. The present study investigated the effect of CHR treatment on I/R-induced ER stress. Mice were subjected to middle cerebral artery occlusion (MCAO) for 45min and received either vehicle or CHR (0.1mg/kg) for 14 days after reperfusion. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) was used to detect apoptotic cells in penumbral tissue. The expression of ER stress-related factors including glucose-regulated protein 78 (GRP78), phosphorylated eukaryotic initiation factor 2α (p-eIF2α), CCAAT-enhancer-binding protein homologous protein (CHOP), and caspase-12 as well as inhibitory κB-α (IκB-α), the inhibitor of NF-κB, was assessed. Our results demonstrated that CHR treatment reduced MCAO-induced upregulation of GRP78, p-eIF2α, CHOP, and caspase-12 in the ischemic brain. Moreover, the TUNEL-positive neuronal cells, which were colocalized with CHOP and caspase-12, decreased in response to CHR treatment, indicating that CHR protects against I/R injury by inhibiting ER stress-associated neuronal apoptosis. In addition, CHR reversed the decrease in IκB-α level induced by MCAO, which was attributed at least in part to the attenuation of translational inhibition induced by eIF2α phosphorylation, indicating that CHR exerts anti-inflammatory effects following I/R by inhibiting ER stress response. These results suggest that attenuation of ER stress may be involved in the mechanisms of neuroprotective effects of CHR.

• Authors: Yongmei Zhao, Yalan Fang, Haiping Zhao, Jincheng Li, Yunxia Duan, Wenjuan Shi, Yuyou Huang, Li Gao, Yumin Luo
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 818 Pg. 1-9 (Jan 05 2018) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 29031902 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Anthraquinones
• Ddit3 protein, mouse
• Endoplasmic Reticulum Chaperone BiP
• Hspa5 protein, mouse
• NF-KappaB Inhibitor alpha
• Transcription Factor CHOP
• Protein Serine-Threonine Kinases
• eIF2alpha kinase, mouse
• chrysophanic acid

Topics

• Animals
• Anthraquinones (pharmacology)
• Apoptosis (drug effects)
• Brain (drug effects, metabolism, pathology)
• Brain Ischemia (complications)
• Endoplasmic Reticulum Chaperone BiP
• Endoplasmic Reticulum Stress (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• NF-KappaB Inhibitor alpha (metabolism)
• Neurons (drug effects, pathology)
• Protein Serine-Threonine Kinases (metabolism)
• Reperfusion Injury (complications, metabolism, pathology)
• Signal Transduction (drug effects)
• Transcription Factor CHOP (metabolism)