Protection against β-amyloid-induced neurotoxicity by naturally occurring Z-ligustilide through the concurrent regulation of p38 and PI3-K/Akt pathways.

Alzheimer's disease (AD) is primarily characterized by the progressive loss of functional neurons in the brain. Therefore, compounds with neuroprotective property may have therapeutic value in treating AD. Z-ligustilide (Z-LIG) is an essential oil originally isolated from umbelliferous plants. In the current study, the neuroprotective effects and underlying mechanisms of Z-LIG against fibrillar aggregates of Aβ25-35 and Aβ1-42-induced neurotoxicity were investigated in both SH-SY5Y cells and differentiated PC12 cells. Z-LIG at 1-30 μM provided an effective neuroprotection, as evidenced by the increase in cell viability, as well as the decrease in LDH release and intracellular accumulation of reactive oxygen species. Additionally, Z-LIG markedly blocked Aβ fibrils-induced condensed nuclei and sub-G1 accumulation suggestive of apoptosis. Furthermore, Z-LIG substantially reversed the activation of phosphorylated p38 and the inhibition of phosphorylated Akt caused by Aβ25-35. LY294002, the specific inhibitor of PI3-K, significantly abrogated the protein expression of up-regulated phosphorylated Akt offered by Z-LIG. Most importantly, siRNA-mediated knockdown of PI3-K and p38 significantly abolished the neuroprotective effects of Z-LIG. The results taken together indicate that Z-LIG protects against Aβ fibrils-induced neurotoxicity possibly through the inhibition of p38 and activation of PI3-K/Akt signaling pathways concurrently. Z-LIG might be a potential candidate for further preclinical study aimed at the prevention and treatment of AD.