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

  • Authors:
    • Jian-Chun Ma
    • Hao-Liang Zhang
    • Hui-Ping Huang
    • Zao-Liang Ma
    • Su-Fang Chen
    • Zhi-Kun Qiu
    • Ji-Sheng Chen
  • View Affiliations

  • Published online on: April 25, 2021     https://doi.org/10.3892/etm.2021.10109
  • Article Number: 677
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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.

Introduction

Depression is a mental health condition with a high clinical incidence. The prevalence of depression in younger patients (age, 12-17 years; incidence rate >12% in the USA in 2015) is higher compared with elderly ones (age, ≥18 years; incidence rate <10% in the USA in 2015) (1,2). Globally, depression is considered to be one of the single largest contributors to non-fatal health losses, accounting for 7.5% of all years lived with disability (YLD). It has been reported that ~80% of depression cases occur in low to middle-income countries (3). There are several typical antidepressant drugs in common usage, including selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), serotonin-noradrenergic reuptake inhibitors (SNRIs) and monoamine oxidase inhibitors (MAOIs) (4). However, ~30-40% of patients do not respond to these drugs during the first 4-6 weeks of treatment. In addition, the efficacy of these drugs is often controversial, while a number of them are accompanied by numerous side effects, including apathy, sedation and cognitive and sleep disorders (5,6). Therefore, more effective and better tolerated antidepressants are urgently needed to treat depression.

Angelica sinensis (Oliv.) Diels (AS) is a well-known traditional Chinese medicine, which has been applied as a treatment for gynecological diseases. The antidepressant-like effects of AS extracts have also been reported (7,8).

Z-ligustilide (LIG; Fig. 1) is the main component of AS, accounting for 2-3.5% of all composite compounds (9-13). Studies have indicated that LIG may significantly improve blood circulation, protect against nerve damage and attenuate painful behavior (11,14-17). The neuroprotective effects of LIG have also been reported in several animal models of cerebral ischemia, indicating that LIG may reduce the infarct size in the ischemic area, decrease edema in the brain and improve neurobehavioral defects (18). Furthermore, LIG is thought to protect against hypoperfusion-induced nerve damage in the cerebral cortex, inhibit cortical neuron apoptosis and maintain the integrity of the neuronal structure (19).

The active antidepressant constituents of AS have been identified and LIG is thought to be one of the most important (20,21). A previous study demonstrated that LIG easily penetrates the blood-brain barrier and quickly enters the brain (22). By applying pharmaceutical analysis and pharmacokinetics, LIG is expected to be a major constituent of antidepressants (23,24).

Progesterone and allopregnanolone are neurosteroids, mediating both the transport of cholesterol from the outer to the inner mitochondrial membrane and the activation of a series of enzymatic reactions to regulate the biosynthesis of neurosteroids (25,26). Studies indicate that reduced levels of progesterone and allopregnanolone are associated with the development of various mental disorders, including anxiety and depression (27,28). Conversely, exogenous administration of progesterone and allopregnanolone may significantly improve depression (29-32).

The present study aimed to evaluate the antidepressant-like effects of LIG and assess its association with the secreted levels of neurosteroids (progesterone and allopregnanolone) in the brain using a rat model.

Materials and methods

Animals

A total of 80 male Sprague-Dawley (SD) rats (weight, 160-200 g; age, 7 weeks) were purchased from the Guangdong Medical Laboratory Animal Center (Guangzhou, China). Prior to experimental procedures, all animals were maintained under controlled environmental conditions for ≥7 days (temperature, 22±2˚C; humidity, 45-65%; 12-h light/dark cycle) with free access to food and water. All animal experiments were conducted according to the Guidelines for the Management and Use of Experimental Animals (33). The experimental procedures were approved by the Animal Care Research Council of Guangdong Pharmaceutical University and complied with the principles of Laboratory Animal Care (34) to minimize the suffering of animals.

Drug preparation and administration

LIG (purity, ≥98%) was obtained from Nanjing Dasf Biotech Ltd. Sertraline (Ser) was purchased from Sigma-Aldrich (Merck KGaA). Mifepristone (Mp) and finasteride (Fin) were acquired from Shanghai Yien Chemical Technology Co., Ltd, and chloral hydrate (CH) from Qingdao Yulong Algae Co., Ltd. Rats were randomized into eight groups. Rats in the normal [not exposed to chronic unpredictable mild stress (CUMS)] and vehicle-treated groups (exposed to CUMS) were treated with 0.9% physiological saline. For the behavioral tests, rats in the Ser positive control group were treated with 15 mg/kg Ser (35,36).

Each behavioral trial consisted of two parts: The pharmacodynamic evaluation of LIG and the evaluation of the effect of Mp and Fin antagonists on LIG. For the pharmacodynamic evaluation of LIG, rats were divided into three groups, where rats were intraperitoneally (i.p.) injected with 10, 20 or 40 mg/kg LIG, as previously described (21,37). For the evaluation of the effect of Mp and Fin antagonists on LIG, rats were divided into the following two groups: i) LIG (20 mg/kg) + Mp (30 mg/kg) (38,39); and ii) LIG (20 mg/kg) + Fin (50 mg/kg) (40,41). LIG, Ser, Mp and Fin were diluted in 0.9% physiological saline. LIG and Ser were administered once daily, while Mp and Fin were administered 1 h prior to the behavioral tests.

CUMS

For CUMS, all rats were treated as previously described (21,42). Briefly, single housed rats were exposed to one stress stimuli per day, which could not be predicted by the animal (Table I). The full experimental procedure lasted for 41 days. Stress stimuli induction occurred from day 1-35 followed by drug administration from day 36-48. The forced swimming test (FST), sucrose preference test (SPT) and open field test (OFT) were performed 1 h following drug administration on day 43-48 (Fig. 2).

Table I

Schedule of chronic unpredictable mild stressors applied.

Table I

Schedule of chronic unpredictable mild stressors applied.

Treatment weekMondayTuesdayWednesdayThursdayFridaySaturdaySunday
1st3145278
2nd1826457
3rd2731864
4th4518732
5th5267148

[i] 1, food deprivation (24 h); 2, water deprivation (24 h); 3, forced swimming (6 min); 4, lighting (24 h); 5, cage tilting (24 h); 6, wet bedding (24 h); 7, rocking bed (200 Hz; 5 min); 8, tail suspending (5 min).

FST (day 43)

FST is a behavioral test used to evaluate the effect of antidepressants. This test was carried out as previously described (21,43,44). Briefly, all rats were placed in separated glass cylinders filled with 20 cm of freshwater at 24±2˚C and forced to swim. Each animal was forced to swim for 6 min and the duration of immobility in the last 4 min was recorded. A rat was considered immobile when stationary or when making only the necessary moves to keep its head above the water.

SPT (day 46)

Low SPT is utilized to evaluate the state of depression (21,43,45). Prior to SPT, two bottles (volume, 200 ml) with 1% sucrose solution (w/v) were provided to each rat for 24 h. The following day, the sucrose solution in one bottle was replaced with pure water. During the test, rats were allowed to drink 1% sucrose solution or pure water for 3 h, and the consumed volume was recorded. Sucrose preference was calculated according to the following equation: Sucrose preference (%)=sucrose intake (g)/[sucrose intake (g) + water intake (g)] x100.

OFT (day 48)

OFTis a behavioral test for evaluating locomotor activity. Due to chronic stress, rats show an unavoidable tendency to reduce their locomotor activity in the open field (21,43,46). The apparatus was placed in a plastic enclosure (dimensions, 100x100x60 cm), with floor and walls painted black. The floor was divided into 25 equal squares, and a 60-W light bulb was hung 40 cm above the center. During the experiment, incidences of crossings (each 25 square crossed with all four paws) and rearings (vertical activity with rats standing on hind legs) were recorded for 3 min.

Determination of progesterone and allopregnanolone levels

Emerging evidence has suggested that the pathogenic mechanisms of depression areassociated withdysfunction ofprogesterone and allopregnanolone biosynthesis (31,32). Following the behavioral tests, rats were anesthetized with CH (400 mg/kg; i.p.) (47) prior to decapitation. Subsequently, the brain regions of interest were removed and dissected on ice. The prefrontal cortex and hippocampus were extracted using 1 ml extraction buffer[containing 50 mM Tris-HCl (pH, 7.4), 150 mM NaCl, 1% NP-40]/100 mg of tissue. To collect the supernatants, all brain samples were homogenized in a tissue homogenizer 20 times with ice-cold lysis buffer [containing 137 mM NaCl, 20 mM Tris-HCl (pH, 8.0), 1% NP40, 10% glycerol, 1 mM PMSF 10 µg/ml aprotinin, 1 µg/mlleupetin and 0.5 mM sodium vanadate]. The homogenate supernatants were centrifuged for 25 min at 4,360 x g and 4˚C. The levels of progesterone (cat. no. ADI-900-011; Enzo Life Sciences, Inc.) and allopregnanolone (cat. no. E1963Ge; EIAab) were determined in the supernatants using ELISA. ELISA was performed in accordance with the manufacturers' instructions and optical density (OD) was measured at a wavelength of 450 nm.

Statistical analysis

All data are presented as the mean ± SEM. Differences among groups were analyzed by one-way analysis of variance (ANOVA) followed by Bonferroni's multiple comparison tests using GraphPad prism 5.0 software (GraphPad Software Inc.). P<0.05 was considered to indicate a statistically significant difference.

Results

Effect of LIG on FST in rats

As shown in Fig. 3, following CUMS, the immobility duration of rats was significantly increased. Consistent with Ser treatment (15 mg/kg; i.p.), LIG administration (20 and 40 mg/kg; i.p.) exhibited antidepressant-like effects on rats, as demonstrated by the reduced immobility time (P<0.0001 for both 20 and 40 mg/kg). Furthermore, treatment with Mp (P=0.0270) and Fin (P=0.0246) significantly reversed the LIG-mediated reduction in immobility time. These results suggested that LIG may produce antidepressant-like effects.

Effect of LIG on SPT in rats

The results of SPT are presented in Fig. 4. Treatment of CUMS rats with Ser (15 mg/kg; i.p.) and LIG (20 and 40 mg/kg; i.p.) notably increased sucrose preference (P=0.0284, 20 mg/kg; P=0.0061, 40 mg/kg). However, Mp (P=0.0209) and Fin (P=0.0238) could significantly reduce sucrose preference in comparison with LIG alone. These findings further confirmed the antidepressant-like effects of LIG.

Effect of LIG on OFT in rats

The antidepressant-like effects of LIG confirmed by OFT are shown in Fig. 5. Following CUMS, rats in the vehicle-treated group showed markedly reduced crossings and rearing time compared with the normal group (P=<0.0001). Similarly to the effects of Ser (15 mg/kg; i.p.), treatment with LIG (20 and 40 mg/kg; i.p.) reversed the number of crossings (20 mg/kg, P=0.0068; 40 mg/kg; P=0.0005; Fig. 5A) and the rearing time (20 mg/kg, P=0.0036; 40 mg/kg, P=0.0013; Fig. 5B) of CUMS rats. In addition the increased number of crossings and rearing time mediated by LIG (20 mg/kg; i.p.) was inhibited by Mp (crossings, P=0.0467; rearing, P=0.0158) and Fin (crossings, P=0.0447; rearing, P=0.0058). The aforementioned results supported the hypothesis that LIG had antidepressant-like effects.

Role of progesterone and allopregnanolone on the antidepressant effects of LIG

The levels of progesterone and allopregnanolone were evaluated at the end of each behavioral test (Fig. 6). The levels of progesterone and allopregnanolone in the prefrontal cortex and hippocampus were significantly decreased in the vehicle-treated group compared with the normal group. However, treatment with Ser (15 mg/kg; i.p.) or LIG, restored the levels of progesterone in the prefrontal cortex (20 mg/kg, P=0.0440; 40 mg/kg, P=0.0024; Fig. 6A) and hippocampus (20 mg/kg, P=0.0020; 40 mg/kg, P=0.0033; Fig. 6B). Similar results were observed in the levels of allopregnanolone in the prefrontal cortex (20 mg/kg, P=0.0033; 40 mg/kg, P<0.0001; Fig. 6C) and hippocampus (20 mg/kg, P=0.0166; 40 mg/kg, P<0.0001; Fig. 6D). Following treatment with Mp, levels of progesterone were decreased in the prefrontal cortex (P=0.0088) and hippocampus (P=0.0017), while Fin notably attenuated the increased levels of allopregnanolone in the prefrontal cortex (P=0.0434) and hippocampus (P=0.0224) compared with LIG alone. Overall, the aforementioned findings indicated that the antidepressant-like effects of LIG were associated with the biosynthesis of progesterone and allopregnanolone in the prefrontal cortex and hippocampus.

Discussion

Studies have indicated that stressful life events, including chronic, low-intensity and long-term daily stressors are involved in the development of depression (48-50). CUMS is a widely used animal model, which is commonly established to simulate the stressors of depression and investigate its pathogenesis (51,52). Therefore, to evaluate the antidepressant effects of LIG, a CUMS rat model was established. FST, SPT and OFT are common behavioral tests applied to evaluate depression in animals (43-46). In the present study, a series of behavioral manifestations of CUMS on FST, SPT and OFT in rats indicated that the depression model was successfully established.

Long-term treatment with antidepressants may reverse CUMS-induced behavioral anomalies. Ser, an SSRI, is used to treat depression-associated symptoms, including depression with or without history of mania (53,54). Ser was selected as a positive control drug. In addition, the effective doses of LIG (20 and 40 mg/kg) and Ser were selected based on a series of experiments. The results suggested that treatment of rats with LIG significantly reduced their immobility and increased their frequency of crossings, rearing time and sucrose preference in comparison with a vehicle. Therefore, the findings of the present study further supported the hypothesis for the antidepressant-like effects of LIG.

Studies showed that long-term treatment with Ser exerted antidepressant-like effects, when administrated 1 h prior to behavioral tests (55,56). Therefore, in the present study the same treatment scheme with Ser was adopted for LIG, and the results confirmed that this treatment approach was effective. Behavioral tests were performed one week following drug administration, suggesting that, similar to SSRI, the antidepressant-like effects of LIG were time-dependent (57,58).

Mp is an anti-progesterone drug, which blocks progesterone through binding to the progesterone receptor. The receptor itself has no progesterone or estrogen activity (38,39). Fin, a steroidal molecule, selectively inhibits type II 5α-reductase, a rate-limiting enzyme, which affects the antidepressant and anti-anxiety activities of several neurosterols, such as allopregnanolone. Treatment with Fin has been associated with several neuropsychiatric side effects, including emotional sensitivity, depression and anxiety (40,41). In the present study the levels of progesterone and allopregnanolone were reduced in the Mp- and Fin-treated groups, respectively. In addition, Mp and Fin antagonized the antidepressant-like effects of LIG, suggesting that Mp and Fin were antagonized the LIG receptor.

Several functional abnormalities have been found in the brain regions implicated in depression, including the prefrontal cortex and hippocampus. These brain regions are comprised of multiple neuron networks, which serve an important role in several processes, including emotional regulation, self-reference processing, memory and internal psychological activities (59-62). Therefore, in the present study, the effect of LIG on the prefrontal cortex and hippocampus was investigated. The results indicated that treatment with LIG significantly increased the levels of progesterone and allopregnanolone in both of these brain areas.

Allopregnanolone is a well-known positive allosteric modulator of γ-aminobutyric acid (GABA) A receptors and is considered to be a selective endogenous modulator of the effects of GABA A on GABA A receptors (63,64). Progesterone upregulates the expression of the GABA A receptor α2, α3, α4 and δ subunits, which are associated with antidepressant-like activities. It has been suggested that the effects of GABA A receptors may be mediated by their conversion to allopregnanolone (65).

Several studies have confirmed an association between reduced levels of neurosteroids (progesterone and allopregnanolone) and depression (66,67). Clinical studies have demonstrated that the levels of progesterone and allopregnanolone are significantly decreased in patients with depression. Therefore, it is considered that the reduced biosynthesis of progesterone and allopregnanolone may be involved in the pathogenesis of depression (30-32). A limited number of studies have focused on the role of progesterone and allopregnanolone in the antidepressant effects of LIG. In the present study levels of progesterone and allopregnanolone were increased following treatment of CUMS rats with LIG, suggesting that the biosynthesis of both neurosteroids could play an important role in the antidepressant effects of LIG. However, more experiments are needed to further elucidate this mechanism. This study could provide novel perspectives on the antidepressant-like effects of LIG and its possible underlying mechanisms.

In the present study the levels of progesterone and allopregnanolone were determined using ELISAs and certain chemicals in the lysis buffer may affect the results of ELISA experiments . Therefore, more accurate methods, such as liquid chromatography-tandem mass spectrometry (LC-MS/MS), should be applied in future studies to determine the levels of neurosteroids in the brain.

The present study evaluated the antidepressant-like effects of LIG on rats by measuring immobility time by FST, sucrose preference by SPT as well as locomotion and rearing time by OFT. Furthermore, the levels of progesterone and allopregnanolone in the prefrontal cortex and hippocampus were evaluated. The results demonstrated that the antidepressant-like effects of LIG could be promoted by the biosynthesis of progesterone and allopregnanolone in the brain. The current study preliminarily explored the antidepressant effects and possible mechanisms of LIG, therefore, further studies should be performed in the future to evaluate the antidepressant-like effects of LIG using more animal models, in order to provide a safe and effective treatment for depression.

Acknowledgements

Not applicable.

Funding

Funding: This study was supported by a grant from the Guangdong Medical Science and Technology Research Fund Project (grant no. A2018352).

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Authors' contributions

JCM and ZKQ conceptualized the study, designed the experiments and wrote the manuscript; HPH, ZLM and SFC performed the experiments. JSC and HLZ analyzed the data. JCM and KSC confirm the authenticity of all the raw data. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Experimental procedures were approved by the Animal Care Research Council of Guangdong Pharmaceutical University.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Weinberger AH, Gbedemah M, Martinez AM, Nash D, Galea S and Goodwin RD: Trends in depression prevalence in the USA from 2005 to 2015: Widening disparities in vulnerable groups. Psychol Med. 48:1308–1315. 2018.PubMed/NCBI View Article : Google Scholar

2 

Wang L, Feng Z, Yang G, Yang Y, Wang K, Dai Q, Zhao M, Hu C, Zhang R, Liu K, et al: Depressive symptoms among children and adolescents in western china: An epidemiological survey of prevalence and correlates. Psychiatry Res. 246:267–274. 2016.PubMed/NCBI View Article : Google Scholar

3 

GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: A systematic analysis for the Global Burden of Disease Study 2015. Lancet. 388:1545–1602. 2016.PubMed/NCBI View Article : Google Scholar

4 

Zhao ZQ, Chiechio S, Sun YG, Zhang KH, Zhao CS, Scott M, Johnson RL, Deneris ES, Renner KJ, Gereau RW IV and Chen ZF: Mice lacking central serotonergic neurons show enhanced inflammatory pain and an impaired analgesic response to antidepressant drugs. J Neurosci. 27:6045–6053. 2007.PubMed/NCBI View Article : Google Scholar

5 

Yang X, Guo Z, Lu J, Zhao B, Fei Y, Li J, Jiang H, Sun L, Wang Y, Sun Y and Bao T: The role of MAPK and dopaminergic synapse signaling pathways in antidepressant effect of electroacupuncture pretreatment in chronic restraint stress rats. Evid Based Complement Alternat Med. 2017:1–9. 2017.PubMed/NCBI View Article : Google Scholar

6 

Ma Z, Ji W, Qu R, Wang M, Yang W, Zhan Z, Fu Q and Ma S: Metabonomic study on the antidepressant-like effects of banxia houpu decoction and its action mechanism. Evid Based Complement Alternat Med. 2(213739)2013.PubMed/NCBI View Article : Google Scholar

7 

Shen J, Zhang J, Deng M, Liu Y, Hu Y and Zhang L: The antidepressant effect of Angelica sinensis extracts on chronic unpredictable mild stress-induced depression is mediated via the upregulation of the BDNF signaling pathway in rats. Evid Based Complement Alternat Med. 2:1–8. 2016.PubMed/NCBI View Article : Google Scholar

8 

Champakaew D, Junkum A, Chaithong U, Jitpakdi A, Riyong D, Wannasan A, Intirach J, Muangmoon R, Chansang A, Tuetun B and Pitasawat B: Assessment of Angelica sinensis (Oliv.) Diels as a repellent for personal protection against mosquitoes under laboratory and field conditions in northern Thailand. Parasit Vectors. 9(373)2016.PubMed/NCBI View Article : Google Scholar

9 

Chen XP, Li W, Xiao XF, Zhang LL and Liu CX: Phytochemical and pharmacological studies on Radix Angelica sinensis. Chin J Nat Med. 11:577–587. 2013.PubMed/NCBI View Article : Google Scholar

10 

Jin M, Zhao K, Huang Q, Xu C and Shang P: Isolation, structure and bioactivities of the polysaccharides from angelica sinensis (oliv.) diels: A review. Carbohydr Polym. 89:713–722. 2012.PubMed/NCBI View Article : Google Scholar

11 

Chao WW and Lin BF: Bioactivities of major constituents isolated from Angelica sinensis (Danggui). Chin Med. 6(29)2011.PubMed/NCBI View Article : Google Scholar

12 

Jeong SY, Kim HM, Lee KH, Kim KY, Huang DS, Kim JH and Seong RS: Quantitative analysis of marker compounds in angelica gigas, angelica sinensis, and angelica acutiloba by hplc/dad. Chem Pharm Bull (Tokyo). 63:504–511. 2015.PubMed/NCBI View Article : Google Scholar

13 

Yi LZ, Liang YZ, Wu H and Yuan DL: The analysis of radix angelicae sinensis (danggui). J Chromatogr A. 1216:1991–2001. 2009.PubMed/NCBI View Article : Google Scholar

14 

Yin J, Wang CY, Mody A, Bao L, Hung SH, Svoronos SA and Tseng Y: The effect of Z-ligustilide on the mobility of human glioblastoma T98G cells. PLoS One. 8(e66598)2013.PubMed/NCBI View Article : Google Scholar

15 

Zhang L, Du JR, Wang J, Yu DK, Chen YS, He Y and Wang CY: Z-ligustilide extracted from radix angelica sinensis decreased platelet aggregation induced by adp ex vivo and arterio-venous shunt thrombosis in vivo in rats. Yakugaku Zasshi. 129:855–859. 2009.PubMed/NCBI View Article : Google Scholar

16 

Wang J, Du JR, Wang Y, Kuang X and Wang CY: Z-ligustilide attenuates lipopolysaccharide-induced proinflammatory response via inhibiting nf-κb pathway in primary rat microglia. Acta Pharmacol Sin. 31:791–797. 2010.PubMed/NCBI View Article : Google Scholar

17 

Gong WX, Zhou YZ, Li X, Gao L, Wang YH, Tian JS and Du GH: Antidepression constituents from angelica sinensis radix in xiaoyao powder. Chin Tradit Herb Drugs. 46:2856–2862. 2015.

18 

Long FY, Shi MQ, Zhou HJ, Liu DL, Sang N and Du JR: Klotho upregulation contributes to the neuroprotection of ligustilide against cerebral ischemic injury in mice. Eur J Pharmacol. 820:198–205. 2018.PubMed/NCBI View Article : Google Scholar

19 

Du JR, Yu Y, Ke Y, Wang CY, Zhu L and Qian ZM: Ligustilide attenuates pain behavior induced by acetic acid or formalin. J Ethnopharmacol. 112:211–214. 2007.PubMed/NCBI View Article : Google Scholar

20 

Zhou Y, Ren Y, Ma Z, Jia G, Gao X, Zhang L and Qin X: Identification and quantification of the major volatile constituents in antidepressant active fraction of xiaoyaosan by gas chromatography-mass spectrometry. J Ethnopharmacol. 141:187–192. 2012.PubMed/NCBI View Article : Google Scholar

21 

Xu F, Peng D, Tao C, Yin D, Kou J, Zhu D and Yu B: Anti-depression effects of danggui-shaoyao-san, a fixed combination of traditional Chinese medicine, on depression model in mice and rats. Phytomedicine. 18:1130–1136. 2011.PubMed/NCBI View Article : Google Scholar

22 

Li J, Yu J, Ma H, Yang N, Li L, Zheng DD, Wu MX, Zhao ZL and Qi HY: Intranasal pretreatment with Z-ligustilide, the main volatile component of rhizoma chuanxiong, confers prophylaxis against cerebral ischemia via nrf2 and hsp70 signaling pathways. J Agric Food Chem. 65:1533–1542. 2017.PubMed/NCBI View Article : Google Scholar

23 

Lu J, Fu L, Qin G, Shi P and Fu W: The regulatory effect of xiaoyao san on glucocorticoid receptors under the condition of chronic stress. Cell Mol Biol (Noisy-le-grand). 64:103–109. 2018.PubMed/NCBI

24 

Zhu X, Jing L, Chen C, Shao M, Fan Q, Diao J, Liu Y, Lv Z and Sun X: Danzhi xiaoyao san ameliorates depressive-like behavior by shifting toward serotonin via the downregulation of hippocampal indoleamine 2,3-dioxygenase. J Ethnopharmacol. 160:86–93. 2015.PubMed/NCBI View Article : Google Scholar

25 

Frye CA, Koonce CJ and Walf AA: Involvement of pregnane xenobiotic receptor in mating-induced allopregnanolone formation in the midbrain and hippocampus and brain-derived neurotrophic factor in the hippocampus among female rats. Psychopharmacology (Berl). 231:3375–3390. 2014.PubMed/NCBI View Article : Google Scholar

26 

Droogleever Fortuyn HA, van Broekhoven F, Span PN, Bäckström T, Zitman FG and Verkes RJ: Effects of phd examination stress on allopregnanolone and cortisol plasma levels and peripheral benzodiazepine receptor density. Psychoneuroendocrinology. 29:1341–1344. 2004.PubMed/NCBI View Article : Google Scholar

27 

Tomaselli G and Vallée M: Stress and drug abuse-related disorders: The promising therapeutic value of neurosteroids focus on pregnenolone-progesterone-allopregnanolone pathway. Front Neuroendocrinol. 55(100789)2019.PubMed/NCBI View Article : Google Scholar

28 

Barak Y and Glue P: Progesterone loading as a strategy for treating postpartum depression. Hum Psychopharmacol. 35(e2731)2020.PubMed/NCBI View Article : Google Scholar

29 

Niwa T, Okada K, Hiroi T, Imaoka S, Narimatsu S and Funae Y: Effect of psychotropic drugs on the 21-hydroxylation of neurosteroids, progesterone and allopregnanolone, catalyzed by rat cyp2d4 and human cyp2d6 in the brain. Biol Pharm Bull. 31:348–351. 2008.PubMed/NCBI View Article : Google Scholar

30 

Dominique CM: Progesterone and allopregnanolone enhance the miniature synaptic release of glycine in the rat hypoglossal nucleus. Eur J Neurosci. 30:2100–2111. 2009.PubMed/NCBI View Article : Google Scholar

31 

Osborne L, Gispen F, Meilman S, Almatrafi M and Payne J: Allopregnanolone and progesterone in pregnancy predict postpartum depression and anxiety. F1000Posters. 6(514)2015.

32 

Schüle C, Nothdurfter C and Rupprecht R: The role of allopregnanolone in depression and anxiety. Prog Neurobiol. 113:79–87. 2014.PubMed/NCBI View Article : Google Scholar

33 

He ZM, Li GP, Zhu DS and Lu SM: Guidelines for the management and use of experimental animals. Beijing, Science and Technology Publications, 2016.

34 

National Research Council US Institute for Laboratory Animal Research: Guide for the Care and Use of Laboratory Animals. Astronomy and Astrophysics, 1996.

35 

Zhang LM, Zhou WW, Ji YJ, Li Y, Zhao N, Chen HX, Xue R, Mei XG, Zhang YZ, Wang HL and Li YF: Anxiolytic effects of ketamine in animal models of posttraumatic stress disorder. Psychopharmacology (Berl). 232:663–672. 2015.PubMed/NCBI View Article : Google Scholar

36 

Miao YL, Guo WZ, Shi WZ, Fang WW, Liu Y, Liu J, Li BW, Wu W and Li YF: Midazolam ameliorates the behavior deficits of a rat posttraumatic stress disorder model through dual 18 kda translocator protein and central benzodiazepine receptor and neurosteroidogenesis. PLoS One. 9(e101450)2014.PubMed/NCBI View Article : Google Scholar

37 

Yu J, Jiang Z, Ning L, Zhao Z, Yang N, Chen L, Ma H, Li L, Fu Y, Zhu H and Qi H: Protective HSP70 induction by Z-ligustilide against oxygen-glucose deprivation injury via activation of the MAPK pathway but not of HSF1. Biol Pharm Bull. 38:1564–1572. 2015.PubMed/NCBI View Article : Google Scholar

38 

Huang J, Zhang Y, Huang Y, Zhang X and Xiao J: Effect of mifepristone on adriamycin resistance in human breast cancer cell line mcf-7/adm in vitro and in vivo. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 35:576–583. 2010.PubMed/NCBI View Article : Google Scholar : (In Chinese).

39 

Fiancette JF, Balado E, Piazza PV and Deroche-Gamonet V: Mifepristone and spironolactone differently alter cocaine intravenous self-administration and cocaine-induced locomotion in C57BL/6J mice. Addict Biol. 15:81–87. 2010.PubMed/NCBI View Article : Google Scholar

40 

Gorin RE, Crabbe JC, Tanchuck MA, Long SL and Finn DA: Effects of finasteride on chronic and acute ethanol withdrawal severity in the wsp and wsr selected lines. Alcohol Clin Exp Res. 29:939–948. 2010.PubMed/NCBI View Article : Google Scholar

41 

Mladenović D, Hrnčić D, Petronijević N, Jevtić G, Radosavljević T, Rašić-Marković A, Puškaš N, Maksić N and Stanojlović O: Finasteride improves motor, EEG, and cellular changes in rat brain in thioacetamide-induced hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol. 307:931–40. 2014.PubMed/NCBI View Article : Google Scholar

42 

Wu X, Tang B, Liao X, Su Z, Lee SM, Cai Y and Li C: Suppressive effects of the supercritical-carbon dioxide fluid extract of chrysanthemum indicum on chronic unpredictable mild stress-induced depressive-like behavior in mice. Food Funct. 10:1212–1224. 2019.PubMed/NCBI View Article : Google Scholar

43 

Yan S, You ZL, Zhao QY, Peng C, He G, Gou XJ and Lin B: Antidepressant-like effects of Sanyuansan in the mouse forced swim test, tail suspension test, and chronic mild stress model. Kaohsiung J Med Sci. 31:605–612. 2015.PubMed/NCBI View Article : Google Scholar

44 

Huang HL, Lim SL, Lu KH and Sheen LY: Antidepressant-like effects of Gan-Mai-Dazao-Tang via monoamine regulatory pathways on forced swimming test in rats. J Tradit Complement Med. 8:53–59. 2018.PubMed/NCBI View Article : Google Scholar

45 

Gao X, Zhuang FZ, Qin SJ, Zhou L, Wang Y, Shen QF, Li M, Villarreal M, Benefield L, Gu SL and Ma TF: Dexmedetomidine protects against learning and memory impairments caused by electroconvulsive shock in depressed rats: Involvement of the NMDA receptor subunit 2B (NR2B)-ERK signaling pathway. Psychiatry Res. 243:446–452. 2016.PubMed/NCBI View Article : Google Scholar

46 

Schulz D: Acute food deprivation separates motor-activating from anxiolytic effects of caffeine in a rat open field test model. Behav Pharmacol. 29:543–546. 2018.PubMed/NCBI View Article : Google Scholar

47 

Choi YB, Kim YI, Lee KS, Kim BS and Kim DJ: Protective effect of epigallocatechin gallate on brain damage after transient middle cerebral artery occlusion in rats. Brain Res. 1019:47–54. 2004.PubMed/NCBI View Article : Google Scholar

48 

Fahey AG and Cheng HW: Effects of social disruption on physical parameters, corticosterone concentrations, and immune system in two genetic lines of white leghorn layers. Poult Sc. 87:1947–1954. 2008.PubMed/NCBI View Article : Google Scholar

49 

Kessler RC: The effects of stressful life events on depression. Ann Rev Psychol. 48:191–214. 1997.PubMed/NCBI View Article : Google Scholar

50 

Kendler KS, Karkowski LM and Prescott CA: Causal relationship between stressful life events and the onset of major depression. Am J Psychiatry. 156:837–841. 1999.PubMed/NCBI View Article : Google Scholar

51 

Qiao H, Li MX, Xu C, Chen HB, An SC and Ma XM: Dendritic spines in depression: What we learned from animal models. Neural Plast. 2016(8056370)2016.PubMed/NCBI View Article : Google Scholar

52 

Antoniuk S, Bijata M, Ponimaskin E and Wlodarczyk J: Chronic unpredictable mild stress for modeling depression in rodents: Meta-analysis of model reliability. Neurosci Biobehav Rev. 99:101–116. 2019.PubMed/NCBI View Article : Google Scholar

53 

De Vane CL, Liston HL and Markowitz JS: Clinical pharmacokinetics of sertraline. Clin Pharmacokinet. 41:1247–1266. 2002.PubMed/NCBI View Article : Google Scholar

54 

Gilliam FG, Black KJ, Carter J, Freedland KE, Sheline YI, Tsai WY and Lustman PJ: A trial of sertraline or cognitive behavior therapy for depression in epilepsy. Ann Neurol. 86:552–560. 2019.PubMed/NCBI View Article : Google Scholar

55 

Qiu ZK, Zhang LM, Zhao N, Chen HX, Zhang YZ, Liu YQ, Mi TY, Zhou WW, Li Y, Yang RF, et al: Repeated administration of AC-5216, a ligand for the 18 kDa translocator protein, improves behavioral deficits in a mouse model of post-traumatic stress disorder. Prog Neuropsychopharmacol Biol Psychiatry. 45:40–46. 2013.PubMed/NCBI View Article : Google Scholar

56 

Zhang LM, Qiu ZK, Zhao N, Chen HX, Liu YQ, Xu JP, Zhang YZ, Yang RF and Li YF: Anxiolytic-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa) in animal models of post-traumatic stress disorder. Int J Neuropsychopharmacol. 17:1659–1669. 2014.PubMed/NCBI View Article : Google Scholar

57 

Oh SJ, Cheng J, Jang JH, Arace J, Jeong M, Shin CH, Park J, Jin J, Greengard P and Oh YS: Hippocampal mossy cell involvement in behavioral and neurogenic responses to chronic antidepressant treatment. Mol Psychiatry. 25:1215–1228. 2019.PubMed/NCBI View Article : Google Scholar

58 

Artigas F: Developments in the field of antidepressants, where do we go now? Eur Neuropsychopharmacol. 25:657–670. 2015.PubMed/NCBI View Article : Google Scholar

59 

Rauch SL, Shin LM and Wright CI: Neuroimaging studies of amygdala function in anxiety disorders. Ann NY Acad Sci. 985:389–410. 2003.PubMed/NCBI View Article : Google Scholar

60 

Bremner JD: Traumatic stress: Effects on the brain. Dialogues Clin Neurosci. 8(445)2006.PubMed/NCBI View Article : Google Scholar

61 

Frodl T, Reinhold E, Koutsouleris N, Reiser M and Meisenzahl EM: Interaction of childhood stress with hippocampus and prefrontal cortex volume reduction in major depression. J Psychiatr Res. 44:799–807. 2010.PubMed/NCBI View Article : Google Scholar

62 

Tebartz van Elst L, Hesslinger B, Thiel T, Geiger E, Haegele K, Lemieux L, Lieb K, Bohus M, Hennig J and Ebert D: Frontolimbic brain abnormalities in patients with borderline personality disorder: A volumetric magnetic resonance imaging study. Biol Psychiatry. 54:163–171. 2003.PubMed/NCBI View Article : Google Scholar

63 

Viero C and Dayanithi G: Neurosteroids are excitatory in supraoptic neurons but inhibitory in the peripheral nervous system: It is all about oxytocin and progesterone receptors. Prog Brain Res. 170:177–192. 2008.PubMed/NCBI View Article : Google Scholar

64 

Qiu ZK, Zhang GH, Zhong DS, He JL, Liu X, Chen JS and Wei DN: Puerarin ameliorated the behavioral deficits induced by chronic stress in rats. Sci Rep. 7(6266)2017.PubMed/NCBI View Article : Google Scholar

65 

Peng HY, Chen GD, Lee SD, Lai CY, Chiu CH, Cheng CL, Chang YS, Hsieh MC, Tung KC and Lin TB: Neuroactive steroids inhibit spinal reflex potentiation by selectively enhancing specific spinal GABA(A) receptor subtypes. Pain. 143:12–20. 2009.PubMed/NCBI View Article : Google Scholar

66 

Klatzkin RR, Morrow AL, Light KC, Pedersen CA and Girdler SS: Histories of depression, allopregnanolone responses to stress, and premenstrual symptoms in women. Biol Psychol. 71:2–11. 2006.PubMed/NCBI View Article : Google Scholar

67 

Hellgren C, Comasco E, Skalkidou A and Sundström-Poromaa I: Allopregnanolone levels and depressive symptoms during pregnancy in relation to single nucleotide polymorphisms in the allopregnanolone synthesis pathway. Horm Behav. 94:106–113. 2017.PubMed/NCBI View Article : Google Scholar

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Volume 22 Issue 1

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Spandidos Publications style
Ma J, Zhang H, Huang H, Ma Z, Chen S, Qiu Z and Chen J: Antidepressant‑like effects of Z‑ligustilide on chronic unpredictable mild stress‑induced depression in rats. Exp Ther Med 22: 677, 2021
APA
Ma, J., Zhang, H., Huang, H., Ma, Z., Chen, S., Qiu, Z., & Chen, J. (2021). Antidepressant‑like effects of Z‑ligustilide on chronic unpredictable mild stress‑induced depression in rats. Experimental and Therapeutic Medicine, 22, 677. https://doi.org/10.3892/etm.2021.10109
MLA
Ma, J., Zhang, H., Huang, H., Ma, Z., Chen, S., Qiu, Z., Chen, J."Antidepressant‑like effects of Z‑ligustilide on chronic unpredictable mild stress‑induced depression in rats". Experimental and Therapeutic Medicine 22.1 (2021): 677.
Chicago
Ma, J., Zhang, H., Huang, H., Ma, Z., Chen, S., Qiu, Z., Chen, J."Antidepressant‑like effects of Z‑ligustilide on chronic unpredictable mild stress‑induced depression in rats". Experimental and Therapeutic Medicine 22, no. 1 (2021): 677. https://doi.org/10.3892/etm.2021.10109