Ferulic Acid Exerts Anti-apoptotic Effects against Ischemic Injury by Activating HSP70/Bcl-2- and HSP70/Autophagy-Mediated Signaling after Permanent Focal Cerebral Ischemia in Rats.

Abstract

This study assessed the anti-apoptotic effects of the administration of ferulic acid (FrA) in rats 30 min before middle cerebral artery occlusion (MCAo) followed by 3 d of ischemia and the involvement of 70 kDa heat shock protein (HSP70)-mediated signaling in the penumbral cortex. Our results demonstrated that FrA pretreatment at doses of 80 mg/kg (FrA-80 mg) and 100 mg/kg (FrA-100 mg) effectively ameliorated neurological functions and reduced the numbers of cytochrome c-, cleaved caspase-3-, and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells in the penumbral cortex 3 d after ischemia. Moreover, FrA-80 mg and FrA-100 mg pretreatment markedly upregulated cytosolic HSP70, Beclin-1, microtubule-associated protein 1 light chain 3 (LC3) A/B-II and autophagy-related protein 5 (Atg5) expression; cytosolic and mitochondrial X-linked inhibitor of apoptosis (XIAP) expression and the Bcl-2/Bax ratio. FrA pretreatment downregulated cytosolic cytochrome c, apoptosis-inducing factor (AIF), procathepsin B, and cathepsin B expression and mitochondrial and cytosolic second mitochondria-derived activator of caspase/direct inhibitor of apoptosis protein-binding protein with a low isoelectric point (Smac/DIABLO) expression in the penumbral cortex. Pretreatment with VER155008, a HSP70 family inhibitor, significantly inhibited the effects of FrA-100 mg on the expression of the aforementioned proteins expression in the penumbral cortex. FrA-80 mg and FrA-100 mg pretreatment exerts neuroprotective effects against caspase-dependent and -independent apoptosis through activating HSP70/Bcl-2- and HSP70/autophagy-induced signaling pathways. Furthermore, the HSP70/Bcl-2- and HSP70/autophagy-induced anti-apoptotic effects of FrA pretreatment can be attributed to the regulation of Bax/cytochrome c/Smac/DIABLO/XIAP/ caspase-3- (or Bax/AIF-) and Beclin-1/LC3A/B-II/Atg5-mediated signaling, respectively, in the penumbral cortex 3 d after permanent MCAo.

• Authors: Chin-Yi Cheng, Shung-Te Kao, Yu-Chen Lee
• Journal: The American journal of Chinese medicine (Am J Chin Med) Vol. 47 Issue 1 Pg. 39-61 ( 2019) ISSN: 1793-6853 [Electronic] Singapore
• PMID: 30612456 (Publication Type: Journal Article)

Chemical References

• Coumaric Acids
• HSP70 Heat-Shock Proteins
• Proto-Oncogene Proteins c-bcl-2
• ferulic acid

Topics

• Angelica sinensis (chemistry)
• Animals
• Apoptosis (drug effects)
• Autophagy (drug effects, genetics)
• Brain Ischemia (genetics, metabolism, physiopathology, prevention & control)
• Cerebral Cortex (metabolism)
• Coumaric Acids (administration & dosage, isolation & purification, pharmacology)
• Gene Expression (drug effects)
• HSP70 Heat-Shock Proteins (genetics, metabolism)
• Male
• Phytotherapy
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Rats, Sprague-Dawley
• Signal Transduction (drug effects, genetics)
• Up-Regulation (drug effects)