Structure of N-palmitoylethanolamide (PEA).

Experimental procedures. Animal grouping and treatments (A). Experimental procedures (B). Animals were exposed to CUMS for 35 days; drug treatments were administered for 28 days. Vehicle, PEA (2.5, 5, 10 mg/kg), fluoxetine (Fxt; 10 mg/kg), or MK886 (MK; 3 mg/kg) were administered for 28 days starting on day 8 after initiating the CUMS procedures.

Changes in body weight and behavioral indicators during the CUMS procedure and after PEA treatment. The body weights of the rats (A) and the results of the sucrose preference test (B) before CUMS and after 35 days of CUMS and 28 days of drug treatment are shown. The effect of PEA on the OFT performance (C and D) of CUMS rats after 35 days of CUMS and 28 days of drug treatment; the distance traveled (C) in the OFT, the locomotor time and the immobility time (D) in the OFT are shown. Veh (vehicle control group), Fxt (10 mg/kg fluoxetine group), PEA 2.5, 5, and 10 (2.5-, 5-, and 10-mg/kg PEA groups), PEA + MK886 (10 mg/kg PEA po + 3 mg/kg MK886 i.p.). Data are presented as the means ± S.E.M., n = 10. ^#P < 0.05; ^##P < 0.01; ^###P < 0.001 vs. NC; *P < 0.05; **P < 0.01; ***P < 0.001 vs. Veh; ^△P < 0.05 vs. 10 mg/kg PEA group.

Effects of PEA on nuclear levels of the PPARα protein and mRNA in the hippocampus of CUMS-induced rats after 35 days of CUMS and 28 days of drug treatment. Levels of the PPARα protein (A and C) were measured using Western blotting and normalized to β-actin levels. The histograms show the relative levels of the PPARα protein. Levels of the PPARα mRNA (B and D) were measured using reverse transcription–polymerase chain reaction. The level of the PPARα mRNA was normalized to GAPDH expression, and the histograms show the relative expression of the PPARα mRNA. The grouping and abbreviation of Veh, Fxt, and 2.5, 5, and 10 PEA groups and the PEA + MK886 group are the same as described in Fig. 3. Data are presented as the means ± S.E.M., n = 4. ^##P < 0.01 vs. NC; *P < 0.05; **P < 0.01 vs. Veh; ^△△P < 0.01 vs. 10 mg/kg PEA group.

Effects of PEA on serum ACTH and CORT levels in CUMS-induced rats. The serum ACTH and CORT levels were measured using ELISAs. The serum ACTH (A) and CORT (B) concentrations are reported in picograms per milliliter and nanograms per milliliter, respectively. The grouping and abbreviation of Veh, Fxt, and 2.5, 5, and 10 PEA groups and the PEA + MK886 group are the same as described in Fig. 3. Data are presented as the means ± S.E.M., n = 8. ^#P < 0.05; ^##P < 0.01; ^###P < 0.001 vs. NC; *P < 0.05; **P < 0.01; ***P < 0.001 vs. Veh; ^△P < 0.05 vs. 10 mg/kg PEA group.

Effects of PEA on representative markers of oxidative stress in the rat hippocampus. The total antioxidant capacity (A), glutathione peroxidase activity (B), superoxide dismutase activity (C), malondialdehyde levels (D) were analyzed. T-AOC levels, GSH-PX activity, and T-SOD activity are reported as units per milligram of protein in tissues, and the MDA level is presented as nanomoles per milligram of protein in tissues. The grouping and abbreviation of Veh, Fxt, and 2.5, 5, and 10 PEA groups and the PEA + MK886 group are the same as described in Fig. 3. Data are presented as the means ± S.E.M., n = 8. ^##P < 0.01; ^###P < 0.001 vs. NC; *P < 0.05; **P < 0.01 vs. Veh; ^△P < 0.05 vs. 10 mg/kg PEA group.

Effects of PEA on BDNF and GDNF levels in the hippocampus of CUMS-induced rats. The BDNF and GDNF levels were determined using ELISAs. The BDNF (A) and GDNF (B) concentrations are reported in picograms per milligram of brain tissue. The grouping and abbreviation of Veh, Fxt, and 2.5, 5, and 10 PEA groups and the PEA + MK886 group are the same as described in Fig. 3. Data are presented as the means ± S.E.M., n = 8. ^#P < 0.05; ^##P < 0.01; ^###P < 0.001 vs. NC; *P < 0.05; **P < 0.01 vs. Veh group.