Korean J Physiol Pharmacol.  2021 May;25(3):217-225. 10.4196/kjpp.2021.25.3.217.

Paeoniflorin ameliorates neuropathic pain-induced depression-like behaviors in mice by inhibiting hippocampal neuroinflammation activated via TLR4/NF-kB pathway

Affiliations
  • 1Center of Morphological Experiment, Medical College of Yanbian University, China
  • 2Department of Neurology, Affiliated Hospital of Yanbian University, Yanji, Jilin 133000, China

Abstract

Neuropathic pain (NP) that contributes to the comorbidity between pain and depression is a clinical dilemma. Neuroinflammatory responses are known to have potentially important roles in the initiation of NP and depressive mood. In this study, we aimed to investigate the effects of paeoniflorin (PF) on NP-induced depression-like behaviors by targeting the hippocampal neuroinflammation through the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-kB) signaling pathway. We used a murine model of NP caused by unilateral sciatic nerve cuffing (Cuff ). PF was injected intraperitoneally once a day for a total of 14 days. Pain and depression-like behavior changes were evaluated via behavioral tests. Pathological changes in the hippocampus of mice were observed by H&E staining. The levels of proinflammatory cytokines in the hippocampus were detected using ELISA. Activated microglia were measured by immunohistochemical staining. The TLR4/NF-kB signaling pathwayassociated protein expression in the hippocampus was detected by western blotting. We found that the PF could significantly alleviate Cuff-induced hyperalgesia and depressive behaviors, lessen the pathological damage to the hippocampal cell, reduce proinflammatory cytokines levels, and inhibit microglial over-activation. Furthermore, PF downregulated the expression levels of TLR4/NF-kB signaling pathwayrelated proteins in the hippocampus. These results indicate that PF is an effective drug for improving the comorbidity between NP and depression.

Keyword

Depression; Hippocampus; Neuralgia; Paeoniflorin; TLR4/NF-kB pathway

Figure

  • Fig. 1 A chemical structure of paeoniflorin (Sigma-Aldrich).

  • Fig. 2 PF treatment alleviates Cuff-induced hypersensitivity to pain. Effects of an intraperitoneal injection of PF (50, 100 mg/kg) on mechanical allodynia (A) and thermal hyperalgesia (B) in Cuff model mice. All values are expressed as mean ± standard deviation. n = 10. PF, paeoniflorin. ***p < 0.001 vs. Sham group; #p < 0.05, ##p < 0.01, ###p < 0.001 vs. Cuff group.

  • Fig. 3 Effects of PF on the depressive behavior of NP model mice. Effects of PF (50, 100 mg/kg) on sucrose preference test (A), forced swimming test (B), and tail suspension test (C) in Cuff model mice. Results are presented as mean ± standard deviation. n = 10. PF, paeoniflorin; NP, neuropathic pain. **p < 0.01, ***p < 0.001 vs. Sham group; #p < 0.05, ##p < 0.01, ###p < 0.001 vs. Cuff group.

  • Fig. 4 PF improves the inflammatory infiltration of hippocampal pyramidal cells and reduces the expression of pro-inflammatory cytokines. Representative photomicrographs of H&E staining in the CA3 (Bar = 100 μm) region of hippocampus in different groups (A). ELISA showed that PF treatment decreased the expression of TNF-α (B), IL-6 (C), and IL-8 (D) caused by Cuff. The data represent the mean ± standard deviation. n = 4. PF, paeoniflorin. ***p < 0.001 vs. Sham group; #p < 0.05, ##p < 0.01, ###p < 0.001 vs. Cuff group.

  • Fig. 5 PF treatment suppressed overactivation of microglia in the CA1 and DG induced by Cuff. Representative images of CA1 and DG (Bar = 100 μm) region sections stained with Iba-1 antibodies (A; black arrows indicate positive microglia). Effect of PF on the number of positive cells for Iba-1 in CA1 (B) and DG (C) regions. Mean ± standard deviation of three experiments. n = 4. PF, paeoniflorin. ***p < 0.001 vs. Sham group; ###p < 0.001 vs. Cuff group.

  • Fig. 6 PF inhibits the increase in expression of TLR4/NF-κB pathway induced by Cuff. The expression of TLR4, MyD88, IκBα, p-NF-κBp65, and NF-κBp65 were determined by western blot analysis in the hippocampus (A). Statistical analysis of relative levels of TLR4 (B), MyD88 (C), p-NF-κBp65 (D), and IκBα (E). Quantitative results are expressed as mean ± standard deviation. n = 3. PF, paeoniflorin. ***p < 0.001 vs. Sham group; ##p < 0.01, ###p < 0.001 vs. Cuff group.


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