Abstract
Accumulating evidence indicates that neurotrophic factor-like substances involved in the induction of neurotrophic factor synthesis may aid in the treatment of neurological disorders, such as Alzheimer's disease. Yokukansan (YKS), a traditional Kampo medicine, has been used for the treatment of anxiety and mood disorders. In the present study, we aimed to identify the signaling pathways associated with YKS-mediated enhancement of nerve growth factor (NGF)-induced neurite extension in rat pheochromocytoma (PC12) cells. Akt and extracellular-regulated kinase 1/2 (ERK1/2) phosphorylation levels were assessed by western blot analysis, in the presence of YKS and following the treatment with TrkA inhibitor, K252a. YKS treatment (NGF+YKS 0.5 group) enhanced NGF-induced neurite outgrowth and phosphorylation/activation of Akt and ERK1/2 in PC12 cells. Moreover, YKS-induced effects were inhibited by the treatment with the TrkA receptor antagonist K252a (NGF+YKS 0.5+K252a group); no significant difference in neurite outgrowth was observed between K252a-treated (NGF+YKS 0.5+K252a group) and NGF-K252a-treated cells (NGF+K252a group). However, neurite outgrowth in K252a-treated cells (NGF+K252a and NGF+YKS 0.5+K252a group) reached only one-third of the level in NGF-treated cells (NGF group). NGF-mediated Akt phosphorylation increased by YKS was also inhibited by K252a treatment (NGF+YKS 0.5+K252a group), but no significant difference in ERK1/2 phosphorylation was observed between NGF-YKS-K252a- and NGF-treated cells (NGF group). Our results indicate that YKS treatment enhanced NGF-induced neurite outgrowth via induction of Akt and ERK1/2 phosphorylation, following the binding of NGF to the TrkA receptor. These findings may be useful in the development of novel therapeutic strategies for the treatment of Alzheimer's disease.
Highlights
Yokukansan (YKS) is a traditional Kampo medicine (Kampo) composed of seven dried medicinal herbs: Atractylodes lancea (A. lancea) rhizome, Poria cocos (P. cocos) sclerotium, Cnidium rhizome, Uncaria hook, Japanese Angelica root, Bupleurum root, and Glycyrrhiza [1]
These results suggest that YKS and nerve growth factor (NGF) acted in a cooperative rather than additive manner to increase the neurite extension
Together with our previous findings [37], these results suggest that the promotion of neurite outgrowth by NGF in PC12 cells is linked to the activation of PI3K, Akt, and extracellular-regulated kinase 1/2 (ERK1/2) signaling pathways
Summary
Yokukansan (YKS) is a traditional Kampo medicine (Kampo) composed of seven dried medicinal herbs: Atractylodes lancea (A. lancea) rhizome, Poria cocos (P. cocos) sclerotium, Cnidium rhizome, Uncaria hook, Japanese Angelica root, Bupleurum root, and Glycyrrhiza [1]. Non-clinical studies [8] have reported that YKS exerts a neuroprotective effect against oxidative stress and endoplasmic reticulum stress [9]. Kubota et al demonstrated that YKS elicits a nerve growth factor (NGF)like effect in vitro [10]. Further studies have documented neuropharmacological acitivity of YKS, including the promotion of neuroplasticity; regulation of neurotransmitter release in serotonergic, glutamatergic, cholinergic, dopaminergic, and gamma-aminobutyric acid neurons; and attenuation of stress and inflammation-induced damage [8,11,12,13,14,15]. The Kazuki Terada, et al.: Yokukansan enhances nerve growth factor-induced neurite outgrowth mechanisms underlying these neuropharmacological actions of YKS remain to be determined
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