Earlier we identified
adenosine monophosphate (
AMP) N(1)-oxide as a unique compound of
royal jelly (RJ) that induces neurite outgrowth (neuritegenesis) from cultured rat
pheochromocytoma PC12 cells via the
adenosine A(2A) receptor. Now, we found that
AMP N(1)-oxide stimulated the phosphorylation of not only
mitogen-activated protein kinase (MAPK) but also that of cAMP/
calcium-response element-
binding protein (CREB) in a dose-dependent manner. Inhibition of MAPK activation by a
MEK inhibitor,
PD98059, did not influence the
AMP N(1)-oxide-induced neuritegenesis, whereas that of
protein kinase A (PKA) by a selective inhibitor,
KT5720, significantly reduced neurite outgrowth.
AMP N(1)-oxide also had the activity of suppressing the growth of PC12 cells, which correlated well with the neurite outgrowth-promoting activity.
KT5720 restored the growth of
AMP N(1)-oxide-treated PC12 cells. It is well known that
nerve growth factor suppresses proliferation of PC12 cells before causing stimulation of neuronal differentiation. Thus,
AMP N(1)-oxide elicited neuronal differentiation of PC12 cells, as evidenced by generation of neurites, and inhibited cell growth through
adenosine A(2A) receptor-mediated PKA signaling, which may be responsible for characteristic actions of RJ.