Effects of sodium ferulate on amyloid-beta-induced MKK3/MKK6-p38 MAPK-Hsp27 signal pathway and apoptosis in rat hippocampus.
OBJECTIVE
To observe the effects of sodium ferulate (SF) on amyloid beta (Abeta)1-40-induced p38 mitogen-activated protein kinase (MAPK) signal transduction pathway and the neuroprotective effects of SF.


METHODS
Rats were injected intracerebroventricularly with Abeta1-40. Six hours after injection, Western blotting was used to determine the expressions of phosphorylated mitogen-activated protein kinase kinase (MKK) 3/MKK6, phospho-p38 MAPK, interleukin (IL)-1beta, phospho-MAPK activating protein kinase 2 (MAPKAPK-2), the 27 kDa heat shock protein (Hsp27), procaspase-9, -3, and -7 cleavage, and poly (ADP-ribose) polymerase (PARP) cleavage. Seven days after injection, Nissl staining was used to observe the morphological change in hippocampal CA1 regions.


RESULTS
Intracerebroventricular injection of Abeta1-40 induced an increase in phosphorylated MKK3/MKK6 and p38 MAPK expressions in hippocampal tissue. These increases, in combination with enhanced interleukin (IL)-1beta protein expression and reduced phospho-MAPKAPK2 and phospho-Hsp27 expression, mediate the Abeta-induced activation of cell death events as assessed by cleavage of procaspase-9, -3, and -7 and caspase-3 substrate PARP cleavage. Pretreatment with SF (100 mg/kg and 200 mg/kg daily, 3 weeks) significantly prevented Abeta1-40-induced increases in phosphorylated MKK3/MKK6 and p38 MAPK expression. The Abeta1-40-induced increase in IL-1beta protein level was attenuated by pretreatment with SF. In addition, Abeta1-40-induced decreases in phosphorylated MAPKAPK2 and Hsp27 expression were abrogated by administration of SF. In parallel with these findings, Abeta1-40-induced changes in activation of caspase-9, caspase-7, and caspase-3 were inhibited by pretreatment with SF.


CONCLUSIONS
SF prevents Abeta1-40-induced neurotoxicity through suppression of MKK3/MKK6-p38 MAPK activity and IL-1beta expression and upregulation of phospho-Hsp27 expression.
Jin
Ying
Y
Department of Pharmacology, Jinzhou Medical College, Jinzhou 121001, China. jyjinying@yahoo.com.cn
Fan
Ying
Y
Yan
En-zhi
EZ
Liu
Zhuo
Z
Zong
Zhi-hong
ZH
Qi
Zhi-min
ZM
D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D002452:Cell Count; D003373:Coumaric Acids / Q000494:pharmacology*; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D007276:Injections, Intraventricular; D053583:Interleukin-1beta / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D048371:MAP Kinase Kinase 3 / Q000378:metabolism*; D048669:MAP Kinase Kinase 6 / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000633:toxicity*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
D016229:Amyloid beta-Peptides; D003373:Coumaric Acids; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D009363:Neoplasm Proteins; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C486114:Hspb1 protein, rat; C078592:amyloid beta-protein (1-40); C004999:ferulic acid