Neuritogenic Monoglyceride Derived from the Constituent of a Marine Fish for Activating the PI3K/ERK/CREB Signalling Pathways in PC12 Cells

Abstract

A neuritogenic monoglyceride, 1-O-(myristoyl) glycerol (MG), was isolated from the head of Ilisha elongate using a PC12 cell bioassay system, and its chemical structure was elucidated using spectroscopic methods. MG significantly induced 42% of the neurite outgrowth of PC12 cells at a concentration of 10 μM. To study the structure-activity relationships of MG, a series of monoglycerides was designed and synthesised. Bioassay results indicated that the alkyl chain length plays a key role in the neuritogenic activity of the monoglycerides. The groups that link the propane-1,2-diol and alkyl chain were also investigated. An ester linkage, rather than an amido one, was found to be optimal for neuritogenic activity. Therefore, 1-O-(stearoyl) glycerol (SG), which induces 57% of the neurite outgrowth of PC12 cells at 10 μM, was determined to be a lead compound for neuritogenic activity. We then investigated the mechanism of action of neurite outgrowth induced by SG on PC12 cells using protein specific inhibitors and Western blot analysis. The mitogen-activated kinase/ERK kinase (MEK) inhibitor U0126 and the phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002 significantly decreased neurite outgrowth. At the same time, SG increased phosphorylation of CREB in protein level. Thus, SG-induced neuritogenic activity depends on the activation of the extracellular-regulated protein kinase (ERK), cAMP responsive element-binding protein (CREB) and PI3K signalling pathways in PC12 cells.

6-shogaol, a neuroactive compound of ginger (jahe gajah) induced neuritogenic activity via NGF responsive pathways in PC-12 cells

“…Priming PC-12 cells with MEK1/2 inhibitors (U0126 and PD98059) and PI3K inhibitor (LY294002) leads to inhibition of both the phosphorylation and activation of MEK/ERK1/2 and PI3K/AKT, respectively, and eventually diminishes the interrelated cellular processes [65–67]. Liao et al (2012) [47] demonstrated that curcumin-induced neuritogenesis was mediated by MEK/ERK1/2 signaling pathway in PC-12 cells.…”

Blockade of Emodin on Amyloid-β 25–35-Induced Neurotoxicity in AβPP/PS1 Mice and PC12 Cells through Activation of the Class III Phosphatidylinositol 3-Kinase/Beclin-1/B-Cell Lymphoma 2 Pathway

“…DMEM and FBS were obtained from Gibco. MTT, Aβ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), PI3K inhibitor LY294002 (purity ≥ 98% by HPLC), and 3-MA (purity ≥ 98% by TLC) were purchased from Sigma-Aldrich. LDH toxicology assay kit and ECL chemiluminescence kit were ordered from Wuhan Boster Biological Engineering Co., Ltd.…”

“…The concentrations of drugs or agents were selected according to the related references. Cells were treated with emodin (10 µM) [13], 30 µM selective PI3K inhibitor LY294002 [30], or 5 mM 3-MA [17] for 1 h prior to 10 µM Aβ 25-35 exposure [31].…”

“…LC3II positive cells in the cortex were decreased significantly by the treatment with both emodin and 3-methyladenine. Furthermore, emodin and 3-methyladenine could increase Bcell lymphoma 2 while decreasing Beclin-1 and hVps34 expressions, which were induced by amyloid-β [25][26][27][28][29][30][31][32][33][34][35] . Small interfering gene silencing Be-clin-1 and B-cell lymphoma 2 confirmed this signaling pathway.…”

“…The LC3-I/LC3-II ratio was used as an indicator of autophagy formation in Aβ-induced AD mice. In the immunohistochemical assay, there was an increase in the number of LC3II positive cells in the cortex sections of AβPP/PS1 mice treated with 10 nM Aβ [25][26][27][28][29][30][31][32][33][34][35] injection when compared with the blank control (p < 0.05 or p < 0.01) (l " Fig. 2).…”