Understanding the Antidepressant Mechanisms of Acupuncture: Targeting Hippocampal Neuroinflammation, Oxidative Stress, Neuroplasticity, and Apoptosis in CUMS Rats

Abstract

Depression is recognized globally as one of the most intractable diseases, and its complexity and diversity make treatment extremely challenging. Acupuncture has demonstrated beneficial effects in various psychiatric disorders. However, the underlying mechanisms of acupuncture's antidepressant action, particularly in depression, remain elusive. Therefore, this study aimed to investigate the effects of acupuncture on chronic unpredictability stress (CUMS)-induced depressive symptoms in rats and to further elucidate its underlying molecular mechanisms. All rats were exposed to CUMS of two stressors every day for 28 days, except for the control group. One hour before CUMS, rats were given a treatment with acupuncture, electroacupuncture, sham-acupuncture, or fluoxetine (2.1 mg/kg). Behavioral tests and biological detection methods were conducted in sequence to evaluate depression-like phenotype in rats. The findings of this study demonstrate that acupuncture therapy effectively ameliorated depression-like behavior induced by CUMS in rats. Additionally, acupuncture exerted a restorative effect on the alterations induced by CUMS in the levels of malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF), cyclic AMP response element-binding protein (CREB), postsynaptic density95 (PSD95), gamma-aminobutyric acid (GABA), and acetylcholine (ACh). Additionally, our findings indicate that acupuncture also modulates the ERK and Caspase-3 apoptotic pathways in the hippocampus of CUMS rats. This study suggests that acupuncture may play a potential preventive role by regulating hippocampal neuroinflammatory response, levels of oxidative stress, apoptotic processes, and enhancing synaptic plasticity.

Keywords: Acupuncture; Apoptosis; Depression; Neuroinflammation; Neuroplasticity; Oxidative Stress.

Fig. 1

Schematic representation of experimental protocol and body weight measurement. A Flow chart of experiment. B The body weight of rats on 0 days. C The body weight of rats on 28 days. D The body weight changes of rats in 6 groups. E Rat restraint device and acupuncture with Shangxing (GV23) and Fengfu (GV16). F Rat restraint device and EA with Shangxing (GV23) and Fengfu (GV16). Results are the mean ± standard error of the mean (x ± s), n = 9 per group. *P < 0.05, ****P < 0.0001, compared to the control group; ^#P < 0.05, ^##P < 0.01, compared to the CUMS group

Fig. 2

Acupuncture ameliorates depressive-behavior rats exposed to CUMS. A, B Rearing numbers and numbers of crossing in the OFT. C The time in the open arms of EPM. D Immobility time in the FST. E The sucrose preference rates in SPT. All the results are expressed as the mean ± standard error of the mean (x ± s), n = 9 per group, *P < 0.05, **P < 0.01, ***P < 0.001, compared to the control group; ^#P < 0.05, ^##P < 0.01, ^###P < 0.001,compared to the CUMS group

Fig. 3

Acupuncture ameliorates oxidative stress in hippocampus and serum of CUMS rats. A, E Content of SOD in hippocampus and serum. B, F Content of CAT in hippocampus and serum. C, G Content of GSH-Px in hippocampus and serum. D, H Content of MDA in hippocampus and serum. n = 6 per group, ***P < 0.001, ****P < 0.0001, compared to the control group; ^#P < 0.05, ^##P < 0.01, compared to the CUMS group

Fig. 4

Acupuncture inhibits CUMS-induced elevation of inflammatory cytokines in hippocampus and serum. A, B Content of IL-1β in hippocampus and serum. C, D Content of IL-6 in hippocampus and serum. E, F Content of TNF-ɑ in hippocampus and serum. n = 6 per group, *P < 0.05, ***P < 0.001, ****P < 0.0001, compared to the control group; ^#P < 0.05, ^##P < 0.01,^###P < 0.001, compared to the CUMS group

Fig. 5

Acupuncture enhances hippocampal synaptic plasticity in CUMS rats. A The expression of BDNF, CREB, and PSD95 protein in each group was detected by Western blot (n = 3 per group). B Analysis of BDNF proteins. C Analysis of CREB proteins. D Analysis of PSD95 proteins. E Content of GABA in hippocampus was detected by Colorimetry. F Content of Ach in hippocampus was detected by Colorimetry (n = 6 per group). All values are presented as mean ± standard error of the mean (x ± s), ***P < 0.001, ****P < 0.0001, compared to the control group; ^#P < 0.05, ^##P < 0.01,^###P < 0.001, compared to the CUMS group

Fig. 6

Acupuncture restored the histopathological injury in hippocampus tissue of CUMS rats. Representative observation of hippocampus sections with H&E staining (× 50 and × 200)

Fig. 7

Effect of acupuncture on ERK and Caspase-3 apoptosis pathways in hippocampus of CUMS rats. A The expression of ERK1/2, p-ERK1/2, Caspase-3, Bax, and Bcl-2 protein in each group was detected by Western blot. B Analysis of ERK1/2 proteins. C Analysis of p-ERK1/2 proteins. D Analysis of Caspase-3 proteins. E Analysis of Bax proteins. F Analysis of Bcl-2 proteins. All values are presented as mean ± standard error of the mean (x ± s), n = 3 per group, ***P < 0.001, compared to the control group; ^#P < 0.05, ^##P < 0.01, compared to the CUMS group

Fig. 8

Schematic diagram of the improvement effect of acupuncture on depression-like behavior in CUMS model