Dl-3-n-Butylphthalide improves lipopolysaccharide-induced depressive-like behavior in rats: involvement of Nrf2 and NF-κB pathways

Abstract

Rationale and objectives: Dl-3-n-Butylphthalide (NBP), a small molecule compound extracted from the seeds of Apium graveolens, possesses a large range of biological effects. Here, we attempted to explore the therapeutic effects of NBP on lipopolysaccharide (LPS)-induced major depressive disorder (MDD) and gain further insight into the underlying mechanisms of the antidepressant effects of NBP.

Methods: We evaluated the effect of NBP against LPS-induced behavioral changes in rats. We also examined the inflammation, oxidative stress, and apoptosis markers and analyzed the Nrf2 and NF-κB pathways in the hippocampus of rats following repeated peripheral immune challenge by LPS for 2 weeks (500 μg/kg every other day).

Results: Our results indicated that repeated LPS administration induced the rats to a depressive-like state and activated inflammatory response, oxidative stress, and apoptosis reactions in the hippocampus. NBP treatment attenuated the LPS-induced abnormal behavior and ameliorated pathogenic processes in rats with MDD. NBP reduced the inflammatory response with inhibited expression of pro-inflammatory cytokines including IL-1β and IL-6 and downregulated the NF-κB signal pathway. Concurrent with the anti-inflammation action, NBP reduced LPS-induced oxidative reactions in the hippocampus and enhanced Nrf2-targeted signals, as evidenced by increased transcription of antioxidant enzymes and decreased malondialdehyde (MDA) production. In addition, NBP inhibited LPS-induced neuronal apoptosis in the rat brain, as evidenced by decreased apoptosis marker Caspase-3 production and TUNEL assay.

Conclusions: These results provide more insight into pathogenesis of MDD and firstly demonstrated the potential antidepressant actions of NBP.

Keywords: Dl-3-n-butylphthalide; Inflammation; Major depressive disorder; Nrf2 signaling.