Abstract: Objective　To investigate the role of N-palmitoylethanolamide (PEA) in regulating the depression-like behavior induced by chronic stress in rats, which is mediated by a potential target peroxisome proliferator-activated receptor alpha (PPARα) of prefrontal cortex (PFC) and hippocampus. Methods　Fifty SD rats are randomly divided into the normal control group, the chronic unpredictable mild stress (CUMS) model group, the fluoxetine group (positive drug control, 10 mg/kg), the PEA group (10 mg/kg), and the PEA+MK886 group (PEA 10 mg/kg+MK886 3 mg/kg). In addition to the normal control group, other groups were given CUMS intervention for 4 weeks to establish depression model. After 1 week of modeling, groups were given corresponding drug intervention for 4 weeks. On the thirty-sixth day, after rats were anesthetized and sacrificed, the prefrontal cortex and hippocampus were quickly separated and preserved. The expression of polysialic acid - nerve cell adhesion molecule (PSA-NCAM) protein in cortex prefrontal lobe (PFC) and hippocampus was observed by immunohistochemical method. The enzyme-linked immunosorbent assay (ELISA) was used to detect brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and nuclear transcription factor (NF-κB) levels in rat PFC or hippocampus. Results　Compared with the CUMS model group, PEA up-regulated the protein expression of PSA-NCAM in prefrontal cortex and hippocampus, and BDNF and GDNF in prefrontal cortex, and down-regulated the levels of TNF-α, IL-1β and NF-κB in prefrontal cortex and hippocampus in the PEA group. Compared with the PEA group, the rats in the MK886 group down-regulated protein expression levels of PSA-NCAM, BDNF and GDNF, and up-regulated the levels of TNF-α, IL-1β and NF-κB of prefrontal cortex or hippocampus. Conclusion　PEA plays a neuroprotective role by regulating PPARα pathway in prefrontal cortex and hippocampus to promote neural plasticity, relieve neuroinflammation, thus improving depression like behavior in CUMS rats.

Key words: depressive disorder, hippocampus, N-palmitoylethanolamine, prefrontal cortex, peroxisome proliferator-activated receptor alpha