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

• Z-ligustilide (Z-LIG) protects against Aβ-induced neurotoxicity in SH-SY5Y cells.
• Z-LIG inhibits Aβ-induced elevation of oxidative stress in SH-SY5Y cells.
• Z-LIG offers neuroprotection via inhibiting P38 pathway and activating PI3-K/Akt pathway.
• Z-LIG may be a potential candidate for further preclinical study aimed at the treatment of Alzheimer's disease.

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.