Low-Intensity Pulsed Ultrasound Enhances Nerve Growth Factor-Induced Neurite Outgrowth through Mechanotransduction-Mediated ERK1/2-CREB-Trx-1 Signaling.
Enhancing the action of nerve growth factor (NGF) is a potential therapeutic approach to neural regeneration. To facilitate neural regeneration, we investigated whether combining low-intensity pulsed ultrasound (LIPUS) and NGF could promote neurite outgrowth, an essential process in neural regeneration. In the present study, PC12 cells were subjected to a combination of LIPUS (1 MHz, 30 or 50 mW/cm2, 20% duty cycle and 100-Hz pulse repetition frequency, 10 min every other day) and NGF (50 ng/mL) treatment, and then neurite outgrowth was compared. Our findings indicated that the combined treatment with LIPUS (50 mW/cm2) and NGF (50 ng/mL) promotes neurite outgrowth that is comparable to that achieved by NGF (100 ng/mL) treatment alone. LIPUS significantly increased NGF-induced neurite length, but not neurite branching. These effects were attributed to the enhancing effects of LIPUS on NGF-induced phosphorylation of ERK1/2 and CREB and the expression of thioredoxin (Trx-1). Furthermore, blockage of stretch-activated ion channels with Gd3+suppressed the stimulating effects of LIPUS on NGF-induced neurite outgrowth and the downstream signaling activation. Taken together, our findings suggest that LIPUS enhances NGF-induced neurite outgrowth through mechanotransduction-mediated signaling of the ERK1/2-CREB-Trx-1 pathway. The combination of LIPUS and NGF could potentially be used for the treatment of nerve injury and neurodegenerative diseases.
Key Laboratory of Biomedical Information Engineering of Ministry of Education, Department of Biomedical Engineering, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China.
Lu
L
Zhao
Key Laboratory of Biomedical Information Engineering of Ministry of Education, Department of Biomedical Engineering, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China. Electronic address: fengyi@mail.xjtu.edu.cn.
Yi
Y
Feng
Key Laboratory of Biomedical Information Engineering of Ministry of Education, Department of Biomedical Engineering, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China.
Hong
H
Hu
Key Laboratory of Biomedical Information Engineering of Ministry of Education, Department of Biomedical Engineering, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China.
Aiwei
A
Shi
Key Laboratory of Biomedical Information Engineering of Ministry of Education, Department of Biomedical Engineering, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China.
Lei
L
Zhang
Key Laboratory of Biomedical Information Engineering of Ministry of Education, Department of Biomedical Engineering, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China. Electronic address: mxwan@mail.xjtu.edu.cn.
Mingxi
M
Wan
D000818:Animals; D015153:Blotting, Western; D050882:CREB-Binding Protein / Q000378:metabolism; D002470:Cell Survival; D004195:Disease Models, Animal; D020935:MAP Kinase Signaling System / Q000502:physiology*; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D009374:Neoplasms, Experimental / Q000628:therapy*; D020932:Nerve Growth Factor / Q000378:metabolism*; D016501:Neurites / Q000502:physiology; D000071446:Neuronal Outgrowth / Q000502:physiology*; D016716:PC12 Cells; D051381:Rats; D013879:Thioredoxins / Q000378:metabolism; D014464:Ultrasonic Therapy / Q000379:methods*
D013879:Thioredoxins; D020932:Nerve Growth Factor; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat
Low-intensity pulsed ultrasound; Nerve growth factor; Neurite outgrowth; Stretch-activated ion channels