Neuroprotective effect of sodium ferulate and signal transduction mechanisms in the aged rat hippocampus.
OBJECTIVE
To investigate whether the age-related increase in interleukin-1beta (IL-1beta) and c-Jun N-terminal kinases (JNK) pathway was coupled with a decrease in cell survival signaling pathways and whether sodium ferulate (SF) treatment was effective in preventing these age-associated changes.


METHODS
Groups of young and aged rats were fed for 4 weeks on a diet enriched in SF (100 mg/kg and 200 mg/kg per day). At the end of the period of dietary manipulation, Western blotting analysis was used to determine the expressions of IL-1beta, phosphorylated mitogen-activated protein kinase kinase (MKK)4, phospho-JNK, phospho-c-Jun, phosphorylated extracellular signal-regulated kinase (ERK1/2), phospho-MEK, phospho-Akt, phosphorylated ribosomal protein S6 protein kinase (p70S6K), and activated caspase-3 and caspase-7. Nissl staining was used to observe the morphological change in hippocampal CA1 regions. Immunohistochemical techniques for glial fibrillary acidic protein (GFAP) and integrin alphaM (OX-42) were used to determine the astrocyte and microglia activation.


RESULTS
IL-1beta protein levels, and phospho-MKK4, phospho-JNK1/2, and phospho-c-Jun were significantly enhanced in hippocampus prepared from age-matched control rats. Increased IL-1beta production and JNK1/2 activation was accompanied by downregulation of MEK/ERK1/2 pathway and Akt/p70S6K pathway, leading to cell apoptosis assessed by activation of caspase-3. Significantly, treatment of aged rats with SF (100 mg/kg and 200 mg/kg per day) for 4 weeks prevented the agerelated increase in IL-1beta and IL-1beta-induced JNK signaling pathway and also the age-related changes in ERK and Akt kinase.


CONCLUSIONS
SF plays neuroprotective roles through suppression of IL-1beta and IL-1beta-induced JNK signaling and upregulation of MEK/ERK1/2 and Akt/p70S6K survival pathways.
Jin
Ying
Y
Department of Pharmacology, Liaoning Medical University, Jinzhou 121001, China. jyjinying@yahoo.com.cn
Yan
En-zhi
EZ
Li
Xiao-ming
XM
Fan
Ying
Y
Zhao
Yan-jie
YJ
Liu
Zhuo
Z
Liu
Wan-zhu
WZ
D000375:Aging / Q000187:drug effects / Q000502:physiology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D048430:Cell Shape; D003373:Coumaric Acids / Q000008:administration & dosage / Q000494:pharmacology*; D004032:Diet; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D015415:Biomarkers; D003373:Coumaric Acids; D016166:Free Radical Scavengers; D053583:Interleukin-1beta; D018696:Neuroprotective Agents; C004999:ferulic acid; D020928:Mitogen-Activated Protein Kinases