Robust Neuritogenesis‐Promoting Activity by Bis(heptyl)‐Cognitin Through the Activation of alpha7‐Nicotinic Acetylcholine Receptor/ERK Pathway

• Published in: CNS neuroscience & therapeutics 2015-06, Vol.21 (6), p.520-529
• Main Authors: Hu, Sheng‐Quan, Cui, Wei, Mak, Shing‐Hung, Choi, Chung‐Lit, Hu, Yuan‐Jia, Li, Gang, Tsim, Karl Wah‐Keung, Pang, Yuan‐Ping, Han, Yi‐Fan
• Format: Article
• Language: English
• Subjects: alpha7 Nicotinic Acetylcholine Receptor - genetics; alpha7 Nicotinic Acetylcholine Receptor - metabolism; Alpha7‐nicotinic acetylcholine receptor; Amyloid beta-Peptides - pharmacology; Animals; Animals, Newborn; Atropine - pharmacology; Bis(heptyl)‐cognitin; Carbazoles - pharmacology; Cell Differentiation - drug effects; Cells, Cultured; Cerebral Cortex - cytology; Cholinergic Agents - pharmacology; Enzyme Inhibitors - pharmacology; Extracellular signal‐regulated kinase; Glycoproteins; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Indole Alkaloids - pharmacology; MAP Kinase Signaling System - drug effects; Nerve Growth Factor - pharmacology; Neurite outgrowth; Neurites - drug effects; Neurodegenerative disorders; Neurons - cytology; Neurons - drug effects; Oligonucleotides - pharmacology; Original; Peptide Fragments - pharmacology; Phosphorylation; Rats; Rats, Sprague-Dawley; Triterpenes - chemistry; Triterpenes - pharmacology
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.12401

Summary Aims Neurodegenerative disorders are caused by progressive neuronal loss in the brain, and hence, compounds that could promote neuritogenesis may have therapeutic values. In this study, the effects of bis(heptyl)‐cognitin (B7C), a multifunctional dimer, on neurite outgrowth were investigated in both PC12 cells and primary cortical neurons. Methods Immunocytochemical staining was used to evaluate the proneuritogenesis effects, and Western blot and short hairpin RNA assays were applied to explore the underlying mechanisms. Results B7C (0.1–0.5 μM) induced robust neurite outgrowth in PC12 cells, as evidenced by the neurite‐bearing morphology and upregulation of growth‐associated protein‐43 expression. In addition, B7C markedly promoted neurite outgrowth in primary cortical neurons as shown by the increase in the length of β‐III‐tubulin‐positive neurites. Furthermore, B7C rapidly increased ERK phosphorylation. Specific inhibitors of alpha7‐nicotinic acetylcholine receptor (α7‐nAChR) and MEK, but not those of p38 or JNK, blocked the neurite outgrowth as well as ERK phosphorylation induced by B7C. Most importantly, genetic depletion of α7‐nAChR significantly abolished B7C‐induced neurite outgrowth in PC12 cells. Conclusion B7C promoted neurite outgrowth through the activation of α7‐nAChR/ERK pathway, which offers novel insight into the potential application of B7C in the treatment of neurodegenerative disorders.