Isorhynchophylline (IRN), an
oxindole alkaloid isolated from Uncaria rhynchophylla, elicited distinct
antidepressant-like activity in mice. The present study aimed to investigate the
antidepressant-like effects of IRN in chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors in mice and to illustrate its possible mechanisms of action. The mice were subjected to CUMS for 6 wk and administered with IRN (20 or 40 mg/kg) daily by oral gavage for 3 wk. The PI3K/
protein kinase B (Akt) inhibitor and
glycogen synthase kinase-3β (GSK-3β) inhibitors were used to determine the involvement of the PI3K/Akt/GSK-3β pathway in the
antidepressant-like effects of IRN in the mice. The results showed that CUMS caused depression-like behaviors in the mice, such as behavioral despair by the forced swim test (FST) and
anhedonia by the
sucrose preference test. In addition, CUMS could significantly reduce the levels of
nerve growth factor and
brain-derived neurotrophic factor but markedly increase the release of TNF-α and
IL-6 in the hippocampus and cerebral cortex of the mice. Western blotting analysis showed that CUMS markedly suppressed the levels of phosphorylated GSK-3β (Ser9) and phosphorylated Akt (Ser473) but significantly enhanced the translocation of NF-κB p65 from cytosol to nuclei in the hippocampus and cerebral cortex of the mice. CUMS could also significantly increase the NF-κB binding activity in the hippocampus and cerebral cortex of the mice, whereas IRN treatment could significantly reverse the behavioral and biochemical changes induced by CUMS in the mice. Moreover, the
antidepressant-like effect of IRN was completely abolished by the PI3K/Akt inhibitor. Combination treatment with IRN and GSK-3β inhibitors in the mice exerted a synergistic anti-immobility action in the FST. The results of mechanistic investigations indicated that the
antidepressant-like action of IRN was mediated, at least in part, by enhancing
neurotrophins and attenuating
neuroinflammation via modulating the PI3K/Akt/GSK-3β pathway.-Xian, Y.-F., Ip, S.-P., Li, H.-Q., Qu, C., Su, Z.-R., Chen, J.-N., Lin, Z.-X.
Isorhynchophylline exerts
antidepressant-like effects in mice via modulating
neuroinflammation and
neurotrophins: involvement of the PI3K/Akt/GSK-3β signaling pathway.