Oridonin is an antidepressant molecule working through the PPAR-γ/AMPA receptor signaling pathway

Oridonin is a diterpene compound that regulates the activity of PPAR-γ (peroxisome proliferator-activated receptor gamma) transcription factor. Cumulative evidence indicates that AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-type glutamate receptors (AMPARs) play an important role in the treatment of depression. In the article, we found that after treatment with oridonin, the immobility time of mice was significantly reduced in the tail suspension test (TST) and the forced-swim test (FST). After five consecutive days of treatment in mice, oridonin significantly enhanced the expression of PPAR-γ, GluA1 (Ser845) phosphorylation, and GluA1 in the total protein extract of the prefrontal cortex (PFC). Blocking PPAR-γ was able to block antidepressant effects of oridonin. In synaptosome fractions of the PFC, oridonin treatment also significantly increased the GluA1 (Ser845) phosphorylation and GluA1 levels. Moreover, antidepressant actions of oridonin were blocked by AMPA receptor-specific antagonist GYKI 52466. This study demonstrates that oridonin regulates PPAR-γ/AMPA receptor signaling in the prefrontal cortex, and that oridonin can be identified as a novel antidepressant with clinical potential.