Sodium ferulate prevents amyloid-beta-induced neurotoxicity through suppression of p38 MAPK and upregulation of ERK-1/2 and Akt/protein kinase B in rat hippocampus.
OBJECTIVE
To observe whether an amyloid beta (Abeta)-induced increase in interleukin (IL)-1beta was accompanied by an increase in the p38 mitogen-activated protein kinase (MAPK) pathway and a decrease in the cell survival pathway, and whether sodium ferulate (SF) treatment was effective in preventing these Abeta-induced changes.


METHODS
Rats were injected intracerebroventricularly with Abeta25-35. Seven days after injection, immunohistochemical techniques for glial fibrillary acidic protein (GFAP) were used to determine the astrocyte infiltration and activation in hippocampal CA1 areas. The expression of IL-1beta, extracellular signal-regulated kinase (ERK), p38 MAPK, Akt/protein kinase B (PKB), Fas ligand and caspase-3 were determined by Western blotting. The caspase-3 activity was measured by cleavage of the caspase-3 substrate (Ac-DEVD-pNA). Reverse transcription-polymerase chain reaction was used to analyze the changes in IL-1beta mRNA levels.


RESULTS
Intracerebroventricular injection of Abeta25-35 elicited astrocyte activation and infiltration and caused a strong inflammatory reaction characterized by increased IL-1beta production and elevated levels of IL-1beta mRNA. Increased IL-1beta synthesis was accompanied by increased activation of p38 MAPK and downregulation of phospho-ERK and phospho-Akt/PKB in hippocampal CA regions prepared from Abeta-treated rats, leading to cell death as assessed by activation of caspase-3. SF significantly prevented Abeta-induced increases in IL-1beta and p38 MAPK activation and also Abeta-induced changes in phospho-ERK and phospho-Akt/PKB expression levels.


CONCLUSIONS
SF prevents Abeta-induced neurotoxicity through suppression of p38 MAPK activation and upregulation of phospho-ERK and phospho-Akt/PKB expression.
Jin
Ying
Y
Department of Ethnopharmacology, China Medical University, Shengyang 110001, China.
Yan
En-zhi
EZ
Fan
Ying
Y
Zong
Zhi-hong
ZH
Qi
Zhi-min
ZM
Li
Zhi
Z
D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D001927:Brain Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003373:Coumaric Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D053222:Fas Ligand Protein; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007276:Injections, Intraventricular; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D008562:Membrane Glycoproteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000633:toxicity*; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048069:Tumor Necrosis Factors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016229:Amyloid beta-Peptides; D003373:Coumaric Acids; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D007375:Interleukin-1; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D012333:RNA, Messenger; D048069:Tumor Necrosis Factors; C074636:amyloid beta-protein (25-35); C004999:ferulic acid; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases