Neuroprotective effect of sodium ferulate and signal transduction mechanisms in the aged rat hippocampus

Aim: To investigate whether the age-related increase in interleukin-1 beta (IL-1 beta) 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-1 beta, 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. Immunchistochemical techniques for glial fibrillary acidic protein (GFAP) and integrin alpha M (OX-42) were used to determine the astrocyte and microglia activation. Results: IL-1 beta 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-1 beta production and JNK1/2 activation was accompanied by down-regulation 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-1 beta and IL-1 beta-induced JNK signaling pathway and also the age-related changes in ERK and Akt kinase. Conclusion: SF plays neuroprotective roles through suppression of IL-1 beta and IL-1 beta-induced JNK signaling and upregulation of MEK/ERK 1/2 and Akt/p70S6K survival pathways.