Puerarin Attenuates Complete Freund’s Adjuvant-Induced Trigeminal Neuralgia and Inflammation in a Mouse Model via Sirt1-Mediated TGF-β1/Smad3 Inhibition

Abstract

Background Puerarin, an active compound of radix puerariae, is a major compound used in Chinese herbal medicines and it has been well known for its pharmacological effects, including antioxidant, anti‑inflammatory, neuroprotective and cardioprotective properties. The aim of the present study was to determine the role of puerarin (Pue) in complete Freund’s adjuvant (CFA)-induced trigeminal neuralgia (TN) and the effects of this compound on Sirt1 activity and on the progression of CFA-induced TN. Methods Mice were injected with CFA on the unilateral face to induce TN. A cell model of inflammation-associated TN was established by interleukin-1β (IL-1β; 10 ng/mL) and tumor necrosis factor-α (TNF-α; 50 ng/mL) stimulation of neurons. Reverse transcription-quantitative PCR and Western blot analyses were performed to analyze mRNA and protein expression levels in trigeminal ganglion and nerve cells. Terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) staining was used to determine nerve cell apoptosis following IL-1β/TNF-α or Pue treatment. Results Pue is a conceivable Sirtuin1 (Sirt1) activator used for the prevention of trigeminal nerve injury that attenuates CFA-induced TN and inflammatory cytokine-evoked overactivation of neuronal inflammation and apoptosis. Treatment of mice with inflammatory cytokines induced upregulation of cleaved caspase-3 protein expression, which was neutralized by Pue supplementation. Both in vivo and in vitro experiments led to the conclusion that Pue modulated Sirt1 activation and repressed transforming growth factor-β1 (TGF-β1) protein expression and drosophila mothers against decapentaplegic homolog3 (Smad3) phosphorylation in order to exert neuroprotection. Conclusion The findings suggested that Pue functioned as a potential Sirt1 activator to improve neuroinflammation-induced TN and neuronal apoptosis via the suppression of TGF-β1/Smad3 activity. The pharmacological activity of Pue provides a new perspective for the effective prevention and treatment of TN.

From Plant to Chemistry: Sources of Antinociceptive Non-Opioid Active Principles for Medicinal Chemistry and Drug Design

“…It is available in different dosage forms for clinical applications [136]. It has been extensively studied as an anti-inflammatory and antioxidant compound [137][138][139][140], and in recent years, its role in It is known that puerarin (2) inhibits calcium influx, improves microcirculation, reduces insulin resistance, scavenges ROS, and counteracts cell death. It is available in different dosage forms for clinical applications [136].…”

“…It is available in different dosage forms for clinical applications [ 136 ]. It has been extensively studied as an anti-inflammatory and antioxidant compound [ 137 , 138 , 139 , 140 ], and in recent years, its role in pain pathways has been investigated. In burn injury rats, puerarin ( 2 ) (100 mg/kg/day i.p., 30 min before burn for 3 days) decreased the up-regulated expression of P2X3 receptor protein and its mRNA in DRG neurons and reduced the primary afferent transmission on P2X3 receptor in DRG, leading to an improvement of thermal and mechanical hypersensitivity [ 141 ].…”

Beneficial effects of natural flavonoids on neuroinflammation

“…These evidences demonstrate that genistein is able to repress neuroinflammation via promoting Nrf2 pathway, as well as suppressing MAPKs and NF-kB pathways. Puerarin (Figure 3), distributed in Pueraria lobata, could reduce the secretion of IL-8, IL-18, MCP-1 and CCL2 in TNF-a plus IL-1b-induced primary nerve cells and the trigeminal ganglions from complete Freund's adjuvant-treated mice through the inhibition of NLRP3, Caspase-1, TGF-b1, NLRP1 protein and Smad3 phosphorylation, and the up-regulation of SIRT1 (133). Another study shows that puerarin could alleviate ICH-induced behavioral defects, drop hematoma volume and histological injury, decrease IL-6, IL-1b, and TNF-a secretion, as well as down-regulate 3-NT, 8-OHdG, and ROS levels in the perihematomal brain tissue of ICH-induced rats via promoting PI3k and Akt phosphorylation, and suppressing the phosphorylation of p65 and the nuclear accumulation of p65 (134).…”

Pharmacological Activity, Pharmacokinetics, and Clinical Research Progress of Puerarin

“…The anti-inflammatory effect of puerarin might be related to the activation of the TGF-β/Smad pathway [ 77 ]. As a potential Sirt1 activator, puerarin improves TN-induced neuroinflammation and neuronal apoptosis by inhibiting TGF-β1/Smad3 activity [ 78 ]. Rats with lumbar disc herniation characterized by ipsilateral mechanical hyperalgesia and abnormal heat pain exhibit persistent radicular pain behavior.…”