Acta Pharmacologica Sinica 2006 October; 27 (10): 1309-1316; doi: 10.1111/j.1745-7254.2006.00414.x

Aim: To observe the effects of sodium ferulate (SF) on amyloid beta (Aβ)_1-40-induced p38 mitogen-activated protein kinase (MAPK) signal transduction pathway and the neuroprotective effects of SF.

Methods: Rats were injected intracerebroventricularly with Aβ_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)-1β, 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 Aβ_1-40 induced an increase in phosphorylated MKK3/MKK6 and p38 MAPK expressions in hippocampal tissue. These increases, in combination with enhanced interleukin (IL)-1β protein expression and reduced phospho-MAPKAPK2 and phospho-Hsp27 expression, mediate the Aβ-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 Aβ_1-40-induced increases in phosphorylated MKK3/MKK6 and p38 MAPK expression. The Aβ_1-40-induced increase in IL-1β protein level was attenuated by pretreatment with SF. In addition, Aβ_1-40-induced decreases in phosphorylated MAPKAPK2 and Hsp27 expression were abrogated by administration of SF. In parallel with these findings, Aβ_1-40-induced changes in activation of caspase-9, caspase-7, and caspase-3 were inhibited by pretreatment with SF.

Conclusion: SF prevents Aβ_1-40-induced neurotoxicity through suppression of MKK3/MKK6-p38 MAPK activity and IL-1β expression and upregulation of phospho-Hsp27 expression.

Keywords: ferulic acid; amyloid; MKK3/MKK6; p38 mitogen-activated protein kinase; inter-leukin-1; 27 kDa heat shock protein; apo-ptosis