Antinociceptive Effects of Ginsenoside Rg3 in a Rat Model of Incisional Pain

Abstract

Background: Ginsenoside Rg3 is an extract of total ginseng saponins, which accounts for 4.7% of all saponins. This study aimed to identify the mechanisms of the antinociceptive effects of ginsenoside Rg3. Methods: Rats were randomly divided into six groups, which were treated with vehicle or 0.5, 1, 1.5, 2, or 4 mg/kg of ginsenoside Rg3 intraperitoneally 2 h after a plantar incision was made. To evaluate the mechanisms of antinociceptive effects, the rats were intraperitoneally injected with naloxone 5 mg/kg, atropine 1 mg/kg, yohimbine 2 mg/kg, mecamylamine 1 mg/kg, prazosin 1 mg/kg, and dexmedetomidine 5 μg/kg. Hyperalgesia produced by the plantar incision was assessed using von Frey filaments 1 day before the incision (BI) and 2 h after the plantar incision (AP); this measurement was repeated at 15, 30, 45, 60, 80, 100 and 120 min, and 24 and 48 h after the injection of ginsenoside Rg3. Serum interleukin-1β (IL-1β) and interleukin-6 (IL-6) levels were measured 1 day before incision and 120 min, 24 h, and 48 h after the injection of ginsenoside Rg3 or vehicle. Results: The mechanical withdrawal threshold (MWT) significantly increased in the group that received ginsenoside Rg3. The dose-MWT response showed a curvilinear, bell-shaped relationship. The maximum MWT was found with the administration of ginsenoside Rg3 at 1.5 mg/kg; MWT decreased to 2 and 4 mg/kg. Yohimbine diminished the analgesic effect of ginsenoside Rg3. Prazosin and dexmedetomidine increased the analgesic effect of ginsenoside Rg3. IL-1β and IL-6 appeared significantly lower relative to control group. Conclusions: Ginsenoside Rg3 has an analgesic effect with a curvilinear dose-response relationship. Alpha 2 adrenergic receptor appeared to be related to the analgesic effect of ginsenoside Rg3. Also, the anti-inflammatory effect of ginsenoside Rg3 could be related to its analgesic effect.

Hormesis and Ginseng: Ginseng Mixtures and Individual Constituents Commonly Display Hormesis Dose Responses, Especially for Neuroprotective Effects

“…These include the effects of R3 (20(s)-Rg3 isomer) on plantar incisional pain in an adult Sprague-Dawley rat model. Inflammatory cytokines levels closely correlated with the pain response ( Figure 35) [113], protection against cigarette smoke extract-induced cell injury in a preconditioning protocol [114], the biphasic enhancement of glucose-stimulated insulin secretion, and AMPK activities by both the 20R and 20S isomers [115] and protection against glutamate-mediated neuronal cell death to HT22 cells, a mouse hippocampal cell line ( Figure 36) [106], and protected against ginsenoside induced cell toxicity in Sprague-Dawley fetal cortical cells. With respect to the biphasic dose response for plantar incision pain, the authors suggested that this could make it more challenging for use in a therapeutic application, noting further the need to document the biphasic dose response in humans.…”

“…The range of endpoints assessed has been broad but dominated by the area of neuroprotection. The areas of greatest interest have been those dealing with cellular/animal models for AD [48] and PD [41,42] disease, followed by stroke [51,52,152,153], neuronal health/regeneration based on studies with spinal cord [24,107]/sciatic nerve [62] injuries, and pain [113]. It is remarkable that this broad range of endpoints from a similarly wide variety of biological models and experimental approaches (e.g., pre-post-conditioning, non-conditioning, different mediators of damage) display hormetic dose responses.…”

“…Effects of IP Administration of Rg3 on the Immunoinflammatory Cytokines (IL-1B and Cytokine 6) in Adult Male Sprague-Dawley Rats at 48 Hours * * Effects of IP administration of Rg3 on the immunoinflammatory cytokines (IL-1B and cytokine 6) in adult male Sprague-Dawley Rats at 48 hours (source:[113]). Each * represent statistical significance for a data point.…”

Molecular Basis of Altered hERG1 Channel Gating Induced by Ginsenoside Rg3

“…However, excessive activation of hERG1 would cause early repolarization of action potentials, essentially mimicking congenital short QT syndrome, a disorder of ventricular repolarization that also increases the risk of lifethreatening arrhythmia (Gaita et al, 2003;Shah, 2010). Rg3 and related ginsenosides have been extensively studied and are claimed to exert a multitude of therapeutic effects (Weber et al, 2012;Nah, 2014;Ahn et al, 2016). Given the plethora of activities associated with Rg3, it is not surprising that this ginsenoside is not a hERG1-specific compound.…”

Anti‐Inflammatory Activity of Rg3‐Enriched Korean Red Ginseng Extract in Murine Model of Sepsis

“…Particularly since the red ginseng fraction we used in our study is enriched in Rg3 so we would like to elucidate the effects of Rg3 as an antinociceptive because it modulates the Ca 2+ channels (part of the pharmacologic basis of ginseng-mediated antinociception) and as an anti-inflammatory agent in the suppression of mouse ear swelling and prevention of vascular inflammatory diseases by decreasing the expression of intercellular adhesion molecule 1 (ICAM–1), vascular cell adhesion molecule-1 (VCAM-1), and P- and E-selectin [ 5 – 8 ]. Moreover, Rg3-induced apoptosis in A549 lung adenocarcinoma via downregulation of epidermal growth factor receptor and in human breast cancer (MDA-MB-231) cells, thus preventing breast cancer [ 9 ].…”