Neuritogenic Activity of Tetradecyl 2,3-Dihydroxybenzoate Is Mediated through the Insulin-Like Growth Factor 1 Receptor/Phosphatidylinositol 3 Kinase/Mitogen-Activated Protein Kinase Signaling Pathway

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-001 induces neurite outgrowth in a rat adrenal pheochromocytoma cell line (PC12). Inhibitors of insulin-like growth factor 1 (IGF-1) receptor, phosphatidylinositol 3-kinase (PI3K), and extracellular signal-regulated kinase (ERK) 1/2 significantly decreased ABG-001-induced neurite outgrowth. Western blot analysis revealed that ABG-001 significantly induced phosphorylation of IGF-1 receptor, protein kinase B (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 inhibitor as well as small-interfering RNA against the IGF-1 receptor. Furthermore, like ABG-001, IGF-1 also induced neurite outgrowth of PC12 cells, and low-dose nerve growth factor 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, and their downstream signaling cascades to induce neurite outgrowth.

Tetradecyl 2,3-Dihydroxybenzoate Improves the Symptoms of Diabetic Mice by Modulation of Insulin and Adiponectin Signaling Pathways

“…The compound contains a long alkyl chain of 14 carbons, two close hydroxyl groups on the benzene ring, and an ester linkage between the ring and alkyl chain ( Luo et al, 2011 ). ABG-001 can induce neurite outgrowth of PC12 cells like NGF via the IGF-1/PI3K/ERK signaling pathway ( Tang et al, 2015 ). In the present study, we tested the anti-diabetic effects of ABG-001 on STZ-induced diabetic mice.…”

“…RNA extraction and cDNA synthesis of white adipose tissue, liver, gastrocnemius muscle, pancreas, and hypothalamus were performed using the methods from previous studies ( Tang et al, 2015 ). The transcript levels were quantified by using CFX96-Touch (Bio-Rad, Hercules, CA, United States) and SYBR Premix EX Taq TM (Takara, Otsu, Japan).…”

“…The protein sample of each liver with 200 mg was prepared and protein concentration was measured as described in a previous study ( Tang et al, 2015 ). One hundred microgram protein of each sample was loaded onto the 10% SDS-PAGE gel and run at 120 V for 60 min.…”

“…ABG-001 (Supplementary Figure 1a ) is a candidate drug for the treatment of dementia, with an NGF-mimic activity and neurogenesis function ( Luo et al, 2011 ). Furthermore, this substance induces the neurite outgrowth of PC12 cells by activating the IGF-1 signaling pathway ( Tang et al, 2015 ). In here, we report the anti-diabetic effect of ABG-001 and its action mechanism of STZ-induced mice.…”

Synthesis and SAR Studies of Neuritogenic Gentiside Derivatives

“…NGF directly bound to the transmembrane-specific tyrosine receptor kinase A, and resulted in phosphorylation of ERKl/2. However, we found that activation of insulin-like growth factor 1 receptor (IGF-1R) is involved in ABG-001, an analogue of 15d induced neurite outgrowth of PC12 cells in recent study, 20) as the chemical structure of 15d is quite similar to that of ABG-001. Therefore, we presumed that the mechanism of 15d on neurite outgrowth is similar to ABG-001.…”