Metabolite 1 of Protopanaxadiol-Type Saponins, an Axonal Regenerative Factor, Stimulates Teneurin-2 Linked by PI3-Kinase Cascade

Abstract

We previously showed that 20-O-b-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 b, Ab(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-2FPI3-kinase cascade.

Kamikihi-to (KKT) Rescues Axonal and Synaptic Degeneration Associated with Memory Impairment in a Mouse Model of Alzheimer's Disease, 5XFAD

“…Efficacies of Kihi-to are almost similar to those of KKT, suggesting active constituents against memory improvement may be involved in overlapped crude drugs between KKT and Kihi-to. We previously showed that one of the constituents of KKT, 20-Oβ-D-glucopyranosyl-20(S)-protopanaxadiol (M1) derived from Ginseng Radix, had axonal extension activity and improved memory disorder and synaptic loss induced by , and that M1 induced axonal outgrowth through the teneurin-2-PI3-kinase cascade (Tohda, Hashimoto, Kuboyama, & Komatsu, 2006). However, many kinds of other compounds also exist in KKT (supplemental Figure 1).…”

Diosgenin is an exogenous activator of 1,25D3-MARRS/Pdia3/ERp57 and improves Alzheimer's disease pathologies in 5XFAD mice

“…Previously, we found that the herbal drug-derived steroidal sapogenins regenerated neurite atrophy and synaptic loss, leading to memory improvement in AD model mice1012. Diosgenin is also a steroidal sapogenin and a major constituent in Dioscorea rhizome and other herbal drugs, such as those from Trigonella spp., Polygonatum spp.…”

Cell-type-specific regulation of raft-associated Akt signaling

“…1, 2, 3 However, aPPD has also been demonstrated to protect neuronal cells against glutamate and N -methyl--aspartate (NMDA)-induced excitotoxicity 4, 5 and to stimulate neuronal cell regeneration by activating the Akt pathway. 6, 7 The mechanism underlying the cell-type-dependent effects of aPPD has not yet been elucidated.…”