title: Protection against β-amyloid-induced neurotoxicity by naturally occurring Z-ligustilide through the concurrent regulation of p38 and PI3-K/Akt pathways.
abstract: 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 Aβ25-35and 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.
authors: Department of Neurology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China. Electronic address: wei_xu2016@163.com.
authors: Wei
authors: W
authors: Xu
authors: Department of Neurology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China.
authors: Li
authors: L
authors: Yang
authors: Department of Neurology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China.
authors: Ji
authors: J
authors: Li
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D020258:Neurotoxicity Syndromes / Q000188:drug therapy; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C074636:amyloid beta-protein (25-35); C027820:ligustilide; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D048051:p38 Mitogen-Activated Protein Kinases; D015107:4-Butyrolactone
keywords: Alzheimer's disease; Neuroprotection; PI3-K/Akt; SH-SY5Y cells; Z-ligustilide; p38