Salvianolic Acids Alleviate Chronic Mild Stress-Induced Depressive-Like Behaviors in Rats

Fengya Zhen^{1,2,3,4,5,†}, Lulu Yu^{1,2,3,4,5,†}, Lan Wang^1,2,3,4,5, Shuo Wang^1,2,3,4,5, Wenting Lu^1,2,3,4,5, Xueyi Wang^1,2,3,4,5,*, Cuixia An^1,2,3,4,5,*

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¹ Department of Psychiatry, the First Hospital of Hebei Medical University, 050031 Shijiazhuang, Hebei, China

² Mental Health Center, Hebei Medical University and Hebei Technical Innovation Center for Mental Health Assessment and Intervention, 050031 Shijiazhuang, Hebei, China

³ Hebei Clinical Research Center for Mental Disorders and Institute of Mental Health, 050031 Shijiazhuang, Hebei, China

⁴ Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, 050031 Shijiazhuang, Hebei, China

⁵ Hebei Brain Ageing and Cognitive Neuroscience Laboratory, 050031 Shijiazhuang, Hebei, China

^*Correspondence: ydyywxy@163.com (Xueyi Wang); acxsunny@sina.com (Cuixia An)
^†These authors contributed equally.

J. Integr. Neurosci. 2023, 22(3), 60; https://doi.org/10.31083/j.jin2203060

Submitted: 21 August 2022 | Revised: 30 September 2022 | Accepted: 11 October 2022 | Published: 8 May 2023

This is an open access article under the CC BY 4.0 license.

Abstract

Background: Salvianolic acids possess anti-inflammatory properties. This study investigated the therapeutic effect of salvianolic acids on chronic mild stress (CMS)-induced depressive-like behaviors in rats and the involvement of toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88). Methods: Eighty male Sprague-Dawley rats were randomly subjected to CMS or non-CMS protocol for 6 weeks. Starting 3 weeks after CMS exposure, the rats in each group were administered saline, fluoxetine (positive control), salvianolic acids, or salvianolic acids + fluoxetine daily for 3 weeks. The body weight change, sucrose preference, and immobility duration in forced swimming were examined before and after drug treatment. The rats were sacrificed at 3 weeks after drug treatment. Quantitative real-time PCR was performed to measure the mRNA levels of TLR4 and MyD88 in the prefrontal cortex and hippocampus of rats. Results: Compared with non-CMS rats, CMS rats had significantly reduced weight gains and sucrose preference, along with significantly increased immobility durations and elevated mRNA levels of TLR4 and MyD88 in both the prefrontal cortex and hippocampus. Treatment with fluoxetine and salvianolic acids, alone or in combination, facilitated weight gains, alleviated depressive-like behaviors, and reduced cerebral TLR4/MyD88 mRNA levels in CMS rats. Besides, fluoxetine and salvianolic acids additively suppressed TLR4/MyD88 mRNA expression in the prefrontal cortex of rats. Furthermore, TLR4 mRNA levels in both hippocampus and prefrontal cortex positively correlated with MyD88 mRNA expression, inflammatory cytokine secretion, and immobility duration but negatively correlated with sucrose preference. Conclusions: Thus, salvianolic acids alleviate depressive-like behaviors, possibly by suppressing TLR4/MyD88-mediated inflammatory signaling in the brain.

Keywords

chronic mild stress

depression

Salvia miltiorrhiza

salvianolic acids

toll-like receptor 4

myeloid differentiation factor 88

Funding

81271489/National Natural Science Foundation of China

H2022206544/Natural Science Foundation of Hebei Province

2022LCTD-A1/Hebei Medical University “14th Five-Year” Clinical Medicine Innovation Research Team Support Program

LS202009/The Hebei Province Government-funded Clinical Medicine Outstanding Talent Training Project

Figures

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Fig. 1.

Salvianolic acids increased body weight gain rates in rats exposed to chronic mild stress (CMS). The body weights were measured before CMS exposure (baseline), 3 weeks post-stress (before drug treatment), and 3 weeks post-treatment. The weight gain rate post-stress was calculated as [(body weight post-stress – baseline body weight)/body weight post-stress] $\times{}$ 100%. The weight gain rate post-treatment was calculated as [(body weight post-treatment – body weight post-stresss)/body weight post-treatment] $\times{}$ 100%. Data are expressed as the mean $\pm{}$ standard deviation (SD). *p $<$ 0.05 vs. nCMS + saline; ${}^{\#}$ p $<$ 0.05 vs. CMS + saline. n = 10. CMS, chronic mild stress; nCMS, non-exposed to chronic mild stress; Sal, salvianolic acids; Flu, fluoxetine.

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J. Integr. Neurosci. Print ISSN 0219-6352 Electronic ISSN 1757-448X