Antidepressant-like effects of Z-ligustilide on chronic unpredictable mild stress-induced depression in rats

Abstract

Depression is a significant public health issue and its neuropathogenesis is associated with the dysfunction of progesterone and allopregnanolone biosynthesis. Z-ligustilide (LIG), one of the main components of the herb Angelica sinensis (Oliv.) Diels (AS), is reported to have antidepressant activities. The present study aimed to evaluate the antidepressant-like effects of LIG via behavioral tests and to measure the levels of progesterone and allopregnanolone in the prefrontal cortex and hippocampus. The results demonstrated that LIG (20 and 40 mg/kg) exerted antidepressant-like effects, confirmed by increased mobility, locomotion, rearing frequency and preference to sucrose. Furthermore, the levels of progesterone and allopregnanolone in the prefrontal cortex and hippocampus were markedly increased following treatment with LIG (20 and 40 mg/kg), indicating that both neurosteroids could serve a significant role in the antidepressant-like effects of LIG.

Keywords: Z-ligustilide; allopregnanolone; depression; progesterone.

Figure 1

Molecular structure of Z-ligustilide.

Figure 2

Schematic depiction of the application of CUMS and behavioral tests. Following CUMS and drug administration, the animals underwent FST (day 43), SPT (day 46) and OFT (day 48). Ser (15 mg/kg; i.p.) and LIG (10, 20, 40 mg/kg; i.p.) were administered daily from day 36 to 48. CUMS, chronic unpredictable mild stress; FST, forced swimming test; SPT, sucrose preference test; OFT, open field test; Ser, sertraline; LIG, Z-ligustilide.

Figure 3

Antidepressant-like effects of LIG on FST in rats. Treatment with LIG (20 and 40 mg/kg; i.p.) significantly reduced immobility time. Mp and Fin reversed the LIG-mediated (20 mg/kg) reduced immobility time. ^##P<0.01 vs. normal group; ^**P<0.01 vs. vehicle-treated group; ^ΔP<0.05, vs. LIG (20 mg/kg) group (n=10). LIG, Z-ligustilide; FST, forced swimming test; Mp, mifepristone; Fin, finasteride; nor, normal; veh, vehicle.

Figure 4

Effect of LIG on SPT in rats. Treatment with LIG (20 and 40 mg/kg) significantly increased sucrose preference. Treatment with Mp or Fin decreased the LIG-mediated (20 mg/kg) sucrose preference. ^##P<0.01 vs. normal group; ^*P<0.05, ^**P<0.01 vs. vehicle-treated group; ^ΔP<0.05, vs. LIG (20 mg/kg) group (n=10). LIG, Z-ligustilide; SPT, sucrose preference test; Mp, mifepristone; Fin, finasteride; nor, normal; veh, vehicle.

Figure 5

Antidepressant-like effects of LIG on OFT in rats. Treatment with LIG (20 and 40 mg/kg) significantly reversed (A) the crossings and (B) rearing time of CUMS rats. Treatment with Mp or Fin reduced the LIG-mediated (20 mg/kg) increase in the number of crossings and rearing time. ^##P<0.01 vs. normal group; ^*P<0.05, ^**P<0.01 vs. vehicle-treated group; ^ΔP<0.05, ^ΔΔP<0.01 vs. LIG (20 mg/kg) group (n=10). LIG, Z-ligustilide; OFT, open field test; CUMS, chronic unpredictable mild stress; Mp, mifepristone; Fin, finasteride; nor, normal; veh, vehicle.

Figure 6

Role of progesterone and allopregnanolone in the antidepressant-like effects of LIG. The levels of (A) progesterone and (B) allopregnanolone in the prefrontal cortex and the levels of (C) progesterone and (D) allopregnanolone in the hippocampus were markedly reversed following treatment with LIG. Mp and Fin attenuated the increased levels of progesterone and allopregnanolone, respectively. ^##P<0.01 vs. normal group; ^*P<0.05 ^**P<0.01 vs. vehicle-treated group; ^ΔP<0.05, ^ΔΔP<0.01 vs. LIG (20 mg/kg) group (n=10). LIG, Z-ligustilide; Mp, mifepristone; Fin, finasteride; nor, normal; veh, vehicle.