Acta Pharmacologica Sinica 2008 December; 29 (12): 1399-1408; doi: 10.1111/j.1745-7254.2008.00848.x

Aim: To investigate whether the age-related increase in interleukin-1b (IL-1b) 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-1b, 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 aM (OX-42) were used to determine the astrocyte and microglia activation.

Results: IL-1b 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-1b 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 age-related increase in IL-1b and IL-1b-induced JNK signaling pathway and also the age-related changes in ERK and Akt kinase.

Conclusion: SF plays neuroprotective roles through suppression of IL-1b and IL-1b-induced JNK signaling and upregulation of MEK/ERK1/2 and Akt/p70S6K survival pathways.

Keywords: ferulic acid; interleukin-1b; c-Jun N-terminal kinases; extracellular signal-regulated kinase; proto-oncogene proteins c-akt