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


CONCLUSIONS
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.
Department of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China.|Institute of New Drug Research, Guangdong Province Key Laboratory of Pharmacodynamic, Constituents of Traditional Chinese Medicine & New Drug Research, College of Pharmacy, Jinan University, Guangdong, China.|The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China.
Sheng-Quan
SQ
Hu
Department of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China.|The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China.
Wei
W
Cui
Department of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China.|The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China.
Shing-Hung
SH
Mak
Department of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China.
Chung-Lit
CL
Choi
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China.
Yuan-Jia
YJ
Hu
National Engineering Laboratory for Modern Silk, College of Textile and Clothing Engineering, Soochow University, Suzhou, China.
Gang
G
Li
Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Hong Kong, China.
Karl Wah-Keung
KW
Tsim
Mayo Cancer Center, Department of Pharmacology, Mayo Clinic, Rochester, MN, USA.
Yuan-Ping
YP
Pang
Department of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China.|The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China.
Yi-Fan
YF
Han
D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001285:Atropine / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018678:Cholinergic Agents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D026121:Indole Alkaloids / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020932:Nerve Growth Factor / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects*; D009841:Oligonucleotides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D002227:Carbazoles; D018678:Cholinergic Agents; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D009841:Oligonucleotides; D010446:Peptide Fragments; D014315:Triterpenes; D064569:alpha7 Nicotinic Acetylcholine Receptor; C075222:amyloid beta-protein (1-42); C494167:cognatine; D049452:Green Fluorescent Proteins; D001285:Atropine; D020932:Nerve Growth Factor; C049985:staurosporine aglycone
Alpha7-nicotinic acetylcholine receptor; Bis(heptyl)-cognitin; Extracellular signal-regulated kinase; Neurite outgrowth; Neurodegenerative disorders