Effect of XingPiJieYu decoction on spatial learning and memory and cAMP-PKA-CREB-BDNF pathway in rat model of depression through chronic unpredictable stress

Abstract

Background: Depression is a mental disorder characterized by a pervasive low mood and loss of pleasure or interest in usual activities, and often results in cognitive dysfunction. The disturbance of cognitive processes associated with depression, especially the impairment of learning and memory, exacerbates illness and increases recurrence of depression. XingPiJieYu (XPJY) is one of the most widely clinical formulas of traditional Chinese medicine (TCM) and can improve the symptoms of depression, including learning and memory. However, its regulatory effects haven't been comprehensively studied so far. Recently, some animal tests have indicated that the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP response element-binding protein (CREB)-brain derived neurotrophic factor (BDNF) signaling pathway in hippocampus is closely related to depression and the pathogenesis of cognitive function impairments. The present study was performed to investigate the effect and mechanism of XPJY on depression and learning and memory in animal model.

Materials: The rat model of depression was established by chronic unpredictable stress (CUS) for 21 days. The rats were randomly divided into six groups: control group, CUS group, CUS + XPJY (1.4 g/kg, 0.7 g/kg and 0.35 g/kg) groups, and CUS + sertraline (10 mg/kg) group. The sucrose preference, open field exploration and Morris water maze (MWM) were tested. The expression of cAMP, CREB, PKA and BDNF protein in hippocampus was examined with Elisa and Western Blot. The mRNA level of CREB and BDNF in hippocampus was measured with PCR.

Results: The results demonstrated that rats subjected to CUS exhibited decreases in sucrose preference, total ambulation, percentage of central ambulation, rearing in the open field test and spatial performance in the MWM. CUS reduced the expression of cAMP, PKA, CREB and BDNF in hippocampus of model rats. These effects could be reversed by XPJY.

Conclusion: The results indicated that XPJY can improve depression and related learning and memory and the effect of XPJY is partly exerted through the cAMP-PKA-CREB-BDNF signaling pathway.

Keywords: BDNF; CAMP; CREB; Chinese herbs; Chronic unpredictable stress; Depression; Learning and memory; PKA.

Fig 1

The HPLC Chromatogram of XPJY

Fig. 2

Effect of XPJY on cAMP following 21 days of chronic unpredictable stress. cAMP was reduced in the chronic unpredictable stress group compared with control group (P < 0.01). Chronic treatment with XPJY 1.4 g/kg significantly increase in cAMP compared with the CUS group (P < 0.01). Sertraline 10 mg/kg group also significantly increase in cAMP compared with the CUS group (P < 0.05). XPJY 0.7 g/kg and 0.7 g/kg treatment did not alter stress-induced cAMP alterations. ++P < 0.01, as compared to the control group; *P < 0.05, as compared to the chronic unpredictable stress group

Fig. 3

Effect of XPJY on hippocampal PKA, CREB and BDNF protein level following 21 days of chronic unpredictable stress. Relative optical density (OD) of PKA/CREB/BDNF to β-actin. PKA, CREB and BDNF were reduced in the chronic unpredictable stress group compared with control group (P < 0.01). Chronic treatment with XPJY 1.4 g/kg significantly increase in PKA, CREB and BDNF compared with the CUS group (P < 0.01). Sertraline 10 mg/kg group also significantly increase in PKA, CREB and BDNF compared with the CUS group (P < 0.01). XPJY 0.7 g/kg group also significantly increase in PKA, CREB and BDNF compared with the CUS group (P < 0.05). XPJY 0.7 g/kg and 0.35 g/kg treatment did not alter stress-induced PKA, BDNF alterations (P > 0.05). ++P < 0.01, as compared to the control group; *P < 0.05, as compared to the chronic unpredictable stress group. Representative immunoblots of PKA/CREB/BDNF and β-actin. 1, control; 2, chronic unpredictable stress; 3, chronic unpredictable stress plus chronic sertraline (10 mg/kg); 4, chronic unpredictable stress plus chronic XPJY (1.4 g/kg); 5, chronic unpredictable stress plus chronic XPJY (0.7 g/kg); 6, chronic unpredictable stress plus chronic XPJY (0.35 g/kg)

Fig. 4

CREB and BDNF mRNA expression following 21 days of chronic unpredictable stress. 1, control; 2, chronic unpredictable stress; 3, chronic unpredictable stress plus chronic XPJY (0.35 g/kg);4, chronic unpredictable stress plus chronic XPJY (0.7 g/kg); 5, chronic unpredictable stress plus chronic XPJY (1.4 g/kg); 6, chronic unpredictable stress plus chronic sertraline (10 mg/kg). CREB and BDNF mRNA were reduced in the chronic unpredictable stress group compared with control group (P < 0.01). Chronic treatment with XPJY 1.4 g/kg significantly increase in CREB and BDNF mRNA compared with the CUS group (P < 0.01). Sertraline 10 mg/kg group also significantly increase in cAMP compared with the CUS group (P < 0.01). Chronic treatment with XPJY 0.7 g/kg significantly increase in CREB and BDNF mRNA compared with the CUS group (P < 0.01 or P < 0.05). XPJY 0.35 g/kg treatment did not alter stress-induced CREB and BDNF mRNA alterations. ++P < 0.01, as compared to the control group; *P < 0.05, **P < 0.01, as compared to the chronic unpredictable stress group