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


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.


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).


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.


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

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The study was supported by the National Natural Science Foundation of China (81602846;81703625) and Natural Science Foundation of Shandong Province (ZR2016HP24).

Author information

Correspondence to Dehua Liao or Pei Jiang.

Ethics declarations

All animal studies were performed in accordance with protocols approved by the Regulations of Experimental Animal Administration issued by the State Committee of Science and Technology of the People’s Republic of China, with the approval of the Ethics Committee in Jining Medical University.

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Mengqi Yang and Ruili Dang are co-first authors.

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Yang, M., Dang, R., Xu, P. et al. Dl-3-n-Butylphthalide improves lipopolysaccharide-induced depressive-like behavior in rats: involvement of Nrf2 and NF-κB pathways. Psychopharmacology 235, 2573–2585 (2018).

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  • Major depressive disorder
  • Dl-3-n-butylphthalide
  • Inflammation
  • Nrf2 signaling