Effects of sodium ferulate on amyloid-beta-induced MKK3/MKK6-p38 MAPK-Hsp27 signal pathway and apoptosis in rat hippocampus

Aim: To observe the effects of sodium ferulate (SF) on amyloid beta (A beta)(1-40) induced p38 mitogen-activated protein kinase (MAPK) signal transduction pathway and the neuroprotective effects of SF. Methods: Rats were injected intracerebroventricularly with A beta(1-40). 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)-1 beta, 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 A beta(1-40) induced an increase in phosphorylated MKK3/MKK6 and p38 MAPK expressions in hippocampal tissue. These increases, in combination with enhanced interleukin (IL)-1 beta protein expression and reduced phospho-MAPKAPK2 and phospho-Hsp27 expression, mediate the A beta-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 A beta(1-40)-induced increases in phosphorylated MKK3/MKK6 and p38 MAPK expression. The A beta(1-40)-induced increase in IL-1 beta protein level was attenuated by pretreatment with SF. In addition, A beta(1-40)-induced decreases in phosphorylated MAPKAPK2 and Hsp27 expression were abrogated by administration of SF. In parallel with these findings, A beta(1-40)-induced changes in activation of caspase-9, caspase-7, and caspase-3 were inhibited by pretreatment with SF. Conclusion: SF prevents A beta(1-40)-induced neurotoxicity through suppression of MKK3/MKK6-p38 MAPK activity and IL-1 beta expression and upregulation of phospho-Hsp27 expression.