Klinische Pharmakologie und Biopharmazeutik

Abstrakt

Mechanisms of Neurotrophic Activities via Low-molecular-weight Compounds: Post-transcriptional Regulation in PC12 Cells and Neurons

Hiroki Maruoka and Koji Shimoke

Recently, it was reported that some low-molecular-weight compounds mimic neurotrophic activities including neurite outgrowth and neuroprotection. Carnosic acid (CA) promotes neurite outgrowth through the activation of Nrf2 in a model of neuron PC12 cells. CA also protects neurons from oxidative stress via the keap/Nrf2 transcriptional pathway. Luteolin induces neurite outgrowth via MAPK, PKC, and cAMP/PKA signaling pathways. In addition, luteolin protects PC12 cells from serum withdrawal-induced oxidative stress. Forskolin-induced neurite outgrowth is mediated by the activation of the PKA signaling pathway, and this PKAmediated neurite outgrowth is achieved by the expression of Nur77 in PC12 cells. In addition, a low concentration of forskolin is closely related to the cAMP-induced protective function against L-DOPA-induced cytotoxicity. The post-transcriptional regulation of gene expression including microRNAs and the acetylation of non-histone protein plays critical roles in neurotrophic activities. Recently, it was revealed that miR-132 modulates luteolin-induced neurite outgrowth via cAMP/PKA- and MAPK-dependent CREB signaling pathways in PC12 cells. Moreover, it has been reported that acetylated Nrf2 binds to the transcriptional activator, CBP/p300 directly, and that Nur77 is acetylated in vivo and in vitro by CBP/p300. The modulation of miR-132 and acetylation of Nrf2 and Nur77 by CBP/p300 may constitute a similar novel regulatory mechanism for low-molecular-weight compounds with neurotrophic activities.