1. ¹Division of Biofunctional Evaluation, Research Center for Ethnomedicine, Institute of Natural Medicine, University of Toyama, Toyama, Japan
2. ²Division of Pharmacognosy, Institute of Natural Medicine, University of Toyama, Toyama, Japan
3. ³21st Century COE Program, University of Toyama, Toyama, Japan

Correspondence: Dr C Tohda, Research Center for Ethnomedicine, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Tel: +81 76 434 7646; Fax: +81 76 434 5068; E-mail: chihiro@ms.toyama-mpu.ac.jp

Received 1 June 2005; Revised 30 August 2005; Accepted 30 August 2005; Published online 2 November 2005.

Abstract

We previously showed that 20-O--D-glucopyranosyl-20(S)-protopanaxadiol (M1), a metabolite of protopanaxadiol-type ginseng saponins by intestinal bacteria had axonal extension activity in degenerated neurons, and improved memory disorder and synaptic loss induced by an active fragment of amyloid , A(25–35). It is unknown how M1 shows these effects in neurons. To clarify the signal transduction mechanism of M1-induced axonal extension, phosphorylated proteins by M1 stimulation were identified because most cellular signal pathways are regulated by phosphorylation/dephosphorylation. The combination of immunoprecipitation and MALDI-TOF-MS revealed that teneurin-2 and mPar3 were specifically phosphorylated by M1 stimulation. Because mPar3 is known as an axonal specifying molecule and to be regulated by phosphatidylinositol 3-kinase (PI3-kinase), the involvement of teneurin-2 and PI3-kinase in the M1 signal was studied. In teneurin-2-deficient cortical neurons, M1-induced axonal extension and PI3-kinase activation were significantly inhibited. In addition, treatment with PI3-kinase inhibitor also reduced M1-induced axonal extension. These results suggest that M1 induces axonal outgrowth through the teneurin-2—PI3-kinase cascade.