Abstract
Tetradecyl 2,3-dihydroxybenzoate (ABG-001) is a lead compound derived from neuritogenic gentisides. In the present study, we investigated the mechanism by which ABG-00 1 induces neurite outgrowth in PC12 cells. Inhibitors of insulin-like growth factor 1 (IGF-1) receptor, phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase 1/2 (ERK1/2) significantly decreased ABG-001-induced neurite outgrowth. Western blot analysis revealed that ABG-001 significantly induced phosphorylation of IGF-1 receptor, AKT, ERK and cAMP responsive element-binding protein (CREB). These effects were markedly reduced by addition of the corresponding inhibitors. We also found that ABG-001-induced neurite outgrowth was reduced by protein kinase C (PKC) inhibitor as well as siRNA against the IGF-1 receptor. Furthermore, like ABG-001, IGF-1 also induced neurite outgrowth of PC12 cells, and low-dose NGF augmented the observed effects of ABG-001 on neurite outgrowth. These results suggest that ABG-001 targets the IGF-1 receptor and activates PI3K, mitogen-activated protein kinase (MAPK) and their downstream signaling cascades to induce neurite outgrowth.
- IGF
- NGF
- MAP Kinase
- CREB
- Pharmacogenomic analyses
- Signaling network analyses
- Imaging with fluorescent indicators (e.g. Ca2+ imaging)
- Structure/function/mechanism
- RNA/siRNA
- Neurodegeneration
- The American Society for Pharmacology and Experimental Therapeutics