MIF-1 (Pro-Leu-Gly-NH(2)) is a tripeptide for which the therapeutic potential in
Parkinson's disease and depression has been indicated by many studies. However, the cellular mechanisms of action of
MIF-1 are not yet clear. Here, we show the specific brain regions responsive to
MIF-1 treatment by c-Fos mapping, and determine the kinetics of cellular signaling by western blotting of pERK, pSTAT3, and c-Fos in cultured neurons. The immunoreactivity of c-Fos was increased 4 hours after
MIF-1 treatment in brain regions critically involved in the regulation of mood, anxiety, depression, and memory. The number of cells activated was greater after peripheral treatment (intravenous delivery) than after intracerebroventricular injection. In cultured SH-SY5Y neuronal cells, c-Fos was induced time- and dose-dependently. The activation of cellular c-Fos was preceded by a transient increase of
mitogen-activated protein kinase pERK but a reduction of phosphorylated Signal Transducer and Activator of Transcription (pSTAT3) initially. We conclude that
MIF-1 can modulate multiple cellular signals including pERK, and pSTAT3 to activate c-Fos. The cellular activation in specific brain regions illustrates the biochemical and neuroanatomical basis underlying the
therapeutic effect of
MIF-1 in
Parkinson's disease and depression.