Paeoniflorin regulates the hypothalamic-pituitary-adrenal axis negative feedback in a rat model of post-traumatic stress disorder

Document Type: Original Article


1 The Research Centre of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China

2 Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China


Objective(s): To investigate the effects of paeoniflorin (PEF) on the hypothalamic-pituitary-adrenal (HPA) axis feedback function of post-traumatic stress disorder (PTSD).
cSingle-prolonged stress (SPS) was used to establish a PTSD-like rat model. The contents of plasma corticosterone (CORT), adrenocorticotropin hormone (ACTH) and corticotropin-releasing hormone (CRH) were measured by ELISA. Glucocorticoid receptor (GR), mineralocorticoid receptor (MR), adrenocorticotropic hormone-releasing factor I receptor (CRF1R), and adrenocorticotropic hormone-releasing factor II receptor (CRF2R) in the hippocampus and amygdala were measured by RT-PCR and immunohistochemistry.
Results: The results showed that on day 8 after SPS, model rats showed enhanced HPA axis negative feedback lasting to day 29. On day 29, plasma CORT levels increased in model rats, while plasma CRH levels had no significant difference on days 8, 22, and 29. The expression of GR and MR of model rats significantly increased in the hippocampus, while the expression of GR, MR, and CRF1R significantly decreased in the amygdala. After 14 days of continuous administration of PEF, the enhanced negative feedback was inhibited, and the plasma CORT level significantly reduced after 21 days of administration. Moreover, PEF could significantly decrease the expression of GR and MR in the hippocampus, and increase the expression of GR, MR, and CRF1R significantly in the amygdala.
Conclusion: PEF could regulate HPA axis dysfunction in a rat model of PTSD, which may be related to regulating expression of GR and MR in the hippocampus and amygdala and regulating expression of CRF1R in the amygdala.


1. Association AP. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington: American Psychiatric Press. 2013.
2. Francati V, Vermetten E, Bremner J. Functional neuroimaging studies in posttraumatic stress disorder: review of current methods and findings. Depress Anxiety 2007; 24:202-218.
3. Yehuda R. Risk and resilience in posttraumatic stress disorder. J Clin Psychiatry 2004; 65:29-36.
4. Inoue T, Kitaichi Y, Koyama T. SSRIs and conditioned fear. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35:1810-1819.
5. Berger W, Mendlowicz MV, Marques-Portella C, Kinrys G, Fontenelle LF, Marmar CR, et al. Pharmacologic alternatives to antidepressants in posttraumatic stress disorder: A systematic review. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33:169-180.
6. Arnett MG, Muglia LM, Laryea G, Muglia LJ. Genetic approaches to hypothalamic-pituitary-adrenal axis regulation. Neuropsychopharmacology 2016; 41:245-260.
7. Bicanic I, Postma R, Sinnema G, De Roos C, Olff M, Van Wesel F, et al. Salivary cortisol and dehydroepiandrosterone sulfate in adolescent rape victims with post traumatic stress disorder. Psychoneuroendocrinology 2013; 38:408-415.
8. Meewisse ML, Reitsma JB, De Vries G. Cortisol and post-traumatic stress disorder in adults: systematic review and meta-analysis. Br J Psychiatry 2007; 191:387-392.
9. Pacella ML, Feeny N, Zoellner L, Delahanty DL. The impact of PTSD treatment on the cortisol awakening response. Depress Anxiety 2014; 31:862-389.
10. Solanki N, Alkadhi I, Atrooz F, Patki G, Salim S. Grape powder prevents cognitive, behavioral, and biochemical impairments in a rat model of posttraumatic stress disorder. Nutr Res 2015; 35:65-75.
11. Zhang Y, Gandhi PR, Standifer KM. Increased nociceptive sensitivity and nociceptin/orphanin FQ levels in a rat model of PTSD. Mol Pain 2012; 8:1-10.
12. Yehuda R, Southwick SM, Krystal JH, Bremner D, Charney DS, Mason JW. Enhanced suppression of cortisol following dexamethasone administration in posttraumatic stress disorder. Am J Psychiatry 1993; 150:83-86.
13. Li JW, Huang SH, Huang WL, Wang WS, Wen G, Gao L, et al. Paeoniflorin ameliorates interferon-alpha-induced neuroinflammation and depressive-like behaviors in mice. Oncotarget 2016; 8:1-19.
14.    Qiu FM, Zhong XM, Mao QQ, Huang Z. The antidepressant-like effects of paeoniflorin in mouse models. Exp Ther Med 2013; 5:1113-1116.
15.    Li J, Li Y, Zhou A, Chen M, Xu S. Study on the toxicity of total glucosides of paeony. Chin Pharmacol Bull 1991; 1:53-55.
16.    Knox D, Stanfield BR, Staib JM, David NP, Keller SM, DePietro T. Neural circuits via which single prolonged stress exposure leads to fear extinction retention deficits. Learn Mem 2016; 23:689-698.
17.    Flandreau E, Toth M. Animal models of PTSD: a critical review. Curr Top Behav Neurosci 2018; 38:47-68.
18.    De Kloet ER. From receptor balance to rational glucocorticoid therapy. Endocrinology 2014; 155:2754-2769.
19.    Bogdan R, Salmeron BJ, Carey CE, Agrawal A, Calhoun VD, Garavan H, et al. Imaging genetics and genomics in psychiatry: a critical review of progress and potential. Biol Psychiatry 2017; 82:165-175.
20.    Liberzon I, Krstov M, Young E. Stress-restress: effects on ACTH and fast feedback. Psychoneuroendocrinology 1997; 22:443-453.
21.    Lu CY, Liu DX, Jiang H, Pan F, Ho CS, Ho RC. Effects of traumatic stress induced in the juvenile period on the expression of gamma-aminobutyric acid receptor type a subunits in adult rat brain. Neural Plast 2017; 2017:1-10.
22.    Pariante CM, Miller AH. Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Biol Psychiatry 2001; 49:391-404.
23.    Zhu Ge Q, Qu J, Su Z, Chen X, Lin C, Zhao F, et al.  The Rat Brain in Stereotaxic Coordinates. 3th ed. Beijing: People’s Medical Publishing House. 2005.
24.    Wu ZY, Tian Q, Li F, Gao JQ, Liu Y, Mao M, et al. Behavioral changes over time in post-traumatic stress disorder: Insights from a rat model of single prolonged stress. Behav Proc 2016; 124:123-129.
25.    Lapiz-Bluhm MD, Bondi CO, Doyen J, Rodriguez GA, Bedard-Arana T, Morilak DA. Behavioural assays to model cognitive and affective dimensions of depression and anxiety in rats. J Neuroendocrinol 2008; 20:1115-1137.
26.    Patki G, Li L, Allam F, Solanki N, Dao AT, Alkadhi K, et al. Moderate treadmill exercise rescues anxiety and depression-like behavior as well as memory impairment in a rat model of posttraumatic stress disorder. Physiol Behav 2014; 130:47-53.
27.    Han F, Ding J, Shi Y. Expression of amygdala mineralocorticoid receptor and glucocorticoid receptor in the single-prolonged stress rats. BMC Neurosci 2014; 15:77-88.
28.    Zhang Q, Chen Z, Wang WW, Deng HH. Temporal characteristics of change in HPA activity among PTSD patients. Adv Psychol Sci 2016; 24:536-546.
29.    Lee B, Sur B, Cho SG, Yeom M, Shim I, Lee H, et al. Ginsenoside Rb1 rescues anxiety-like responses in a rat model of post-traumatic stress disorder. J Nat Med 2016; 70:133-144.
30.    Zhao M, Yu Z, Zhang Y, Huang X, Hou J, Zhao Y, et al. Iron-induced neuronal damage in a rat model of post-traumatic stress disorder. Neurosci 2016; 330:90-99.
31.    Hassell JE, Nguyen KT, Gates CA, Lowry CA. The impact of stressor exposure and glucocorticoids on anxiety and fear. Curr Top Behav Neurosci 2019; 43:271-321.
32.    Inda C, Armando NG, Dos Santos Claro PA, Silberstein S. Endocrinology and the brain: corticotropin-releasing hormone signaling. Endocr Connect 2017; 6:99-120.
33.    Bale T, Vale W. CRF and CRF receptors: Role in stress responsivity and other behaviors. Annu Rev Pharmacol Toxicol 2004; 44:525-557.
34.    Griffin M, Resick P, Yehuda R. Enhanced cortisol suppression following dexamethasone administration in domestic violence survivors. Am J Psychiatry 2005; 162:1192-1199.
35.    Li HZ, Wu JL, Zhang YL, Li LF, Zhou YF. Pituitary-adrenal responses to low-dose dexamethasone suppression tests in depressive patients and posttraumatic stress disorder. Nerv Dis Ment Health 2005; 5:420-421.
36.    Dekel S, Ein-Dor T, Gordon KM, Rosen JB, Bonanno GA. Cortisol and PTSD symptoms among male and female high-exposure 9/11 survivors. J Trauma Stress 2013; 26:621-625.
37.    Fan QY, Xue R, Li Y, Zhang TT, Ge HX, Li YF, et al. Establishment of female rat model for post-traumatic stress disorder induced by single prolonged stress. Chin J Pharmacol Toxicol 2013; 27:715-719.
38.    Eagle AL, Fitzpatrick CJ, Perrine SA. Single prolonged stress impairs social and object novelty recognition in rats. Behav Brain Res 2013; 256:591-597.
39.    Liberzon I, López J, Flagel S, Vázquez D, Young E. Differential regulation of hippocampal glucocorticoid receptors mRNA and fast feedback: relevance to post-traumatic stress disorder. J Neuroendocrinol 1999; 11:11-17.
40.    De Kloet E, Vreugdenhil E, Oitzl M, Joëls M. Brain corticosteroid receptor balance in health and disease. Endocr Rev 1998; 19:269-301.
41.    Knox D, Nault T, Henderson C, Liberzon I. Glucocorticoid receptors and extinction retention deficits in the single prolonged stress model. Neurosci 2012; 223:163-173.
42.    Han F, Ding JL, Shi YX. Expression of amygdala mineralocorticoid receptor and glucocorticoid receptor in the single prolonged stress rats. BMC Neurosci 2014; 77:1471-2202.
43.    Myers B, McKlveen JM, Herman JP. Glucocorticoid actions on synapses, circuits, and behavior: implications for the energetics of stress. Front Neuroendocrinol 2014; 35:180-196.
44.    Souza RR, Noble LJ, McIntyre CK. Using the single prolonged stress model to examine the pathophysiology of PTSD. Front Pharmacol 2017; 8:615-624.
45.    Xiang XJ, Li LJ, Hao W. Long-term potentiation is associated with stress and drug dependence. Chin J Behav Med Sci 2002; 11:597-598.
46.    Tsatsanis C, Dermitzaki E, Venihaki M, Chatzaki E, Minas V, Gravanis A, et al. The corticotropin-releasing factor (CRF) family of peptides as local modulators of adrenal function. Cell Mol Life Sci 2007; 64:1638-1655.
47.    Dunlop BW, Wong A. The hypothalamic-pituitary-adrenal axis in PTSD: pathophysiology and treatment interventions. Prog Neuropsychopharmacol Biol Psychiatry 2019; 89:361-379.
48.    Henckens MJ, Deussing JM, Chen A. Region-specific roles of the corticotropin-releasing factor-urocortin system in stress. Nat Rev Neurosci 2016; 17:636-651.
49.    Walker DL, Miles LA, Davis M. Selective participation of the bed nucleus of the stria terminalis and CRF in sustained anxiety-like versus phasic fear-like responses. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33:1291-1308.
50.    Grillon C, Hale E, Lieberman L, Davis A, Pine DS, Ernst M. The CRH1 antagonist GSK561679 increases human fear but not anxiety as assessed by startle. Neuropsychopharmacology 2015; 40:1064-1071.
51. Imel ZE, Laska K, Jakupcak M, Simpson TL. Supplemental material for meta-analysis of dropout in treatments for posttraumatic stress disorder. J Consult Clin Psychol 2013; 81:394-404.