iridoids and Neuralgia

Neuropathic pain (NP) is a common disorder among individuals worldwide, but there is still no effective treatment for NP. The EGFR pathway promotes NP nociceptive sensitization and represents a potential therapeutic target. Geniposide is abundant in natural plants and has various pharmacological activities, such as analgesia and anti-inflammation properties, which can improve NP, but the specific mechanisms have not been elucidated. The present study first predicted and molecularly docked geniposide targets, suggesting that geniposide may play a role in improving NP by targeting EGFR. This study further clarified that geniposide alleviates NP and improves the inflammatory response using a chronic constriction injury (CCI) model, whereas the administration of an EGFR agonist weakens the above effects of geniposide. Analysis of transcriptome data further suggests that geniposide not only improves CCI symptoms by reducing EGFR/PI3K/AKT pathway activity but also may exert anti-inflammatory effects by inhibiting the Ca

Topics: Animals; ErbB Receptors; Iridoids; Neuralgia; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley

Neuropathic pain has been shown to be modulated by the activation of the chemokine C-X-C motif ligand 12 (CXCL12)/chemokine CXC receptor 4 (CXCR4) dependent nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome. Loganin, an iridoid glycoside, was proven to prevent neuropathic pain, but its underlying mechanisms related to NLRP3 activation are still unknown.. This study investigated the underlying mechanisms of loganin's effect on chronic constriction injury (CCI)-induced NLRP3 inflammasome activation in the spinal cord.. Sprague-Dawley rats were randomly divided into four groups: sham, CCI, sham + loganin, and CCI + loganin. Loganin (5 mg/kg/day) was administered intraperitoneally starting the day after surgery. Paw withdrawal threshold (PWT) and latency (PWL) were assessed before CCI and on days 1, 3, 7 and 14 after CCI. Spinal cords were collected for western blots and immunofluorescence studies.. Loganin prevented CCI-attenuated PWT and PWL, suggesting improved mechanical allodynia and thermal hyperalgesia. The expression of CXCL12, CXCR4, thioredoxin-interacting protein (TXNIP), NLRP3 inflammasome (NLRP3, ASC, and caspase-1), IL-1β, and IL-18 were enhanced on day 7 after CCI, and all were reduced after loganin treatment. Dual immunofluorescence also showed that increased CXCL12, CXCR4, and NLRP3 were colocalized with NeuN (neuronal marker), GFAP (astrocyte marker), and Iba1 (microglial marker) on day 7 in the ipsilateral spinal dorsal horn (SDH). These immunoreactivities were attenuated in loganin-treated rats. Moreover, loganin decreased the assembly of NLRP3/ASC inflammasome after CCI in the ipsilateral SDH. Loganin appears to attenuate CCI-induced neuropathic pain by suppressing CXCL12/CXCR4-mediated NLRP3 inflammasome.. Our findings suggest that loganin might be a suitable candidate for managing CCI-provoked neuropathic pain.

Topics: Animals; Cell Cycle Proteins; Hyperalgesia; Inflammasomes; Iridoids; Neuralgia; NLR Family, Pyrin Domain-Containing 3 Protein; Rats; Rats, Sprague-Dawley; Receptors, Chemokine; Receptors, CXCR4; Spinal Cord

Loganin is an iridoid glycoside with antioxidant, anti-inflammatory, glucose-lowering activities which may address the pathological mechanisms of painful diabetic neuropathy (PDN) related to inflammation, oxidative stress, and hyperglycemia. This study investigated the underlying mechanisms of action of loganin on PDN. The in vivo model of PDN was established by streptozotocin-nicotinamide (STZ-NA) induction in Sprague Dawley (SD) rats. Subsequently, loganin (5 mg/kg) was administered by daily intraperitoneal injection. High-glucose stimulated human SH-SY5Y cells co-incubated with loganin were used to mimic the in vitro model of PDN. Loganin improved PDN rats' associated pain behaviors (allodynia and hyperalgesia), insulin resistance index (HOMA-IR), and serum levels of superoxide dismutase (SOD), catalase and glutathione. Loganin also reduced pain-associated channel protein Ca

Topics: Animals; Antioxidants; Behavior, Animal; Blood Glucose; Body Weight; Calcitonin Gene-Related Peptide; Calcium Channels, T-Type; Cell Line, Tumor; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Fasting; Humans; Hyperglycemia; Inflammation; Inflammation Mediators; Insulin; Insulin Resistance; Iridoids; Male; Neuralgia; Neuroglia; NF-kappa B; Niacinamide; Oxidative Stress; Rats, Sprague-Dawley; Signal Transduction; Spinal Cord Dorsal Horn; Streptozocin

Peripheral nerve injury can produce chronic and ultimately neuropathic pain. The chronic constriction injury (CCI) model has provided a deeper understanding of nociception and chronic pain. Loganin is a well-known herbal medicine with glucose-lowering action and neuroprotective activity.. This study investigated the molecular mechanisms by which loganin reduced CCI-induced neuropathic pain.. Sprague-Dawley rats were randomly divided into four groups: sham, sham+loganin, CCI and CCI+loganin. Loganin (1 or 5 mg/kg/day) was injected intraperitoneally once daily for 14 days, starting the day after CCI. For behavioral testing, mechanical and thermal responses were assessed before surgery and on d1, d3, d7 and d14 after surgery. Sciatic nerves (SNs) were collected to measure proinflammatory cytokines. Proximal and distal SNs were collected separately for Western blotting and immunofluorescence studies.. Thermal hyperalgesia and mechanical allodynia were reduced in the loganin-treated group as compared to the CCI group. Loganin (5 mg/kg/day) prevented CCI from inducing proinflammatory cytokines (TNF-α, IL-1β), inflammatory proteins (TNF-α, IL-1β, pNFκB, pIκB/IκB, iNOS) and receptor (TNFR1, IL-1R), adaptor protein (TRAF2) of TNF-α, and Schwann cell demyelination and axonal damage. Loganin also blocked IκB phosphorylation (p-IκB). Double immunofluorescent staining further demonstrated that pNFκB/pIκB protein was reduced by loganin in Schwann cells on d7 after CCI. In the distal stumps of injured SN, Schwann cell demyelination was correlated with pain behaviors in CCI rats.. Our findings indicate that loganin improves CCI-induced neuroinflammation and pain behavior by downregulating TNF-α/IL-1β-dependent NF-κB activation.

Topics: Analgesics, Non-Narcotic; Animals; Chronic Pain; Constriction; Cytokines; Hyperalgesia; Interleukin-1beta; Iridoids; Male; Neuralgia; NF-kappa B; Rats, Sprague-Dawley; Schwann Cells; Sciatic Nerve; Tumor Necrosis Factor-alpha

Neuropathic pain caused by traumatic neuromas is an extremely intractable clinical problem. Disorderly scar tissue accumulation and irregular and immature axon regeneration around the injury site mainly contribute to traumatic painful neuroma formation. Therefore, successfully preventing traumatic painful neuroma formation requires the effective inhibition of irregular axon regeneration and disorderly accumulation of scar tissue. Considering that chondroitin sulfate proteoglycans (CSPGs) can act on the growth cone and effectively inhibit axon regeneration, the authors designed and manufactured a CSPG-gelatin blocker to regulate the CSPGs' spatial distribution artificially and applied it in a rat model after sciatic nerve neurectomy to evaluate its effects in preventing traumatic painful neuroma formation.. Sixty female Sprague Dawley rats were randomly divided into three groups (positive group: no covering; blank group: covering with gelatin blocker; and CSPG group: covering with the CSPG-gelatin blocker). Pain-related factors were evaluated 2 and 8 weeks postoperatively (n = 30). Neuroma growth, autotomy behavior, and histological features of the neuromas were assessed 8 weeks postoperatively (n = 30).. Eight weeks postoperatively, typical bulb-shaped neuromas did not form in the CSPG group, and autotomy behavior was obviously better in the CSPG group (p < 0.01) than in the other two groups. Also, in the CSPG group the regenerated axons showed a lower density and more regular and improved myelination (p < 0.01). Additionally, the distribution and density of collagenous fibers and the expression of α-smooth muscle actin were significantly lower in the CSPG group than in the positive group (p < 0.01). Regarding pain-related factors, c-fos, substance P, interleukin (IL)-17, and IL-1β levels were significantly lower in the CSPG group than those in the positive and blank groups 2 weeks postoperatively (p < 0.05), while substance P and IL-17 remained lower in the CSPG group 8 weeks postoperatively (p < 0.05).. The authors found that CSPGs loaded in a gelatin blocker can prevent traumatic neuroma formation and effectively relieve pain symptoms after sciatic nerve neurotomy by blocking irregular axon regeneration and disorderly collagenous fiber accumulation in the proximal nerve stump. These results indicate that covering the proximal nerve stump with CSPGs may be a new and promising strategy to prevent traumatic painful neuroma formation in the clinical setting.

Topics: Administration, Topical; Animals; Axons; Behavior, Animal; Chondroitin Sulfate Proteoglycans; Cicatrix; Female; Ganglia, Spinal; Gelatin; Growth Cones; Interleukin-17; Interleukin-1beta; Iridoids; Nerve Regeneration; Neuralgia; Neuroma; Peripheral Nervous System Neoplasms; Random Allocation; Rats; Rats, Sprague-Dawley; rho GTP-Binding Proteins; Sciatic Neuropathy; Sciatica; Single-Blind Method

Neuropathic pain is a severe health problem for which there is a lack of effective therapy. Ozone and Gardenia fruits have been used separately in pain relief for many years; however, their underlying mechanisms remain unclear. To investigate the pain‑relieving effects of combined ozone and Gardenia, a chronic constriction sciatic nerve injury (CCI) rat model was constructed and treated with ozone and gardenoside (Ozo&Gar), which is a compound found in Gardenia fruits. A total of 70 rats were randomly divided into five groups: Control (Ctrl), Ctrl + Ozo&Gar, Sham, CCI, and CCI + Ozo&Gar. The rats in the Ctrl + Ozo&Gar and CCI + Ozo&Gar groups were administered an intravenous injection of 30 µg/ml ozone and 300 µmol/l gardenoside. The rats in the Ctrl, Sham and CCI groups were administered the same volume of saline. Pain behavior, mechanical hyperalgesia, thermal hyperalgesia, and the protein expression levels of P2X3 and P2X7 purine receptors in L4‑L5 dorsal root ganglion (DRG) were determined 15 days post‑surgery. The results demonstrated that treatment with a combination of ozone and gardenoside increased mechanical withdrawal threshold and thermal withdrawal latency, thus confirming their pain‑relieving effects. In addition, a significant increase in the mRNA and protein expression levels of P2X3 and P2X7 was detected in the DRG of rats in the CCI group compared with in the control groups; however, following treatment with a combination of ozone and gardenoside, the mRNA and protein expression levels of P2X3 and P2X7 receptors were significantly reduced compared with in the CCI group. These results indicated that the mechanism underlying the pain‑relieving effects of ozone and gardenoside may be mediated by inhibition of P2X3 and P2X7 purine receptors in the DRG. This finding suggested that ozone and gardenoside may be considered potential drug candidates that target P2X3 and P2X7 purine receptors.

Topics: Animals; Gene Expression Regulation; Iridoids; Male; Neuralgia; Oxidants, Photochemical; Ozone; Pain Measurement; Peripheral Nerve Injuries; Rats; RNA, Messenger; Sciatic Neuropathy

Here, using rat model, we investigated the roles of gardenoside in the chronic constriction injury (CCI) of the ischiadic nerve.. Bennett and Xie's unilateral sciatic nerve CCI model was used in this study. A total of 60 rats were divided into control group (CN), sham group (Sham), CCI group, and gardenoside administrated CCI group. An aliquot of 5 mL gardenoside solution was administrated through gavage once per day for 14 d. Mechanical withdrawal threshold (MWT) and the thermal withdrawal latency (TWL) were detected. The levels of inducible nitric oxide synthase (iNOS), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) in spinal fluid were detected by ELISA. By using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot, we analyzed the expression of P2X purinoceptor 3 and 7 (P2X3 and P2X7 receptors) in different groups. The expression of p-ERK/ERK and p-p38/p38 were also detected by western blot.. We found out that gardenoside could significantly improve the sciatica by partially restore the decrease of MWT and TWL in CCI rats. The levels of iNOS, IL-1β, and TNF-α were higher in CCI group (p < .05). The expressions of P2X3 and P2X7 were significantly increased in the CCI rats compared to control rats (p < .05). The levels of p-ERK/ERK and p-p38/p38 were also obviously increased in CCI group (p < .05). After treated with the gardenoside, these increases were decreased.. These results indicated that gardenoside may be able to relief CCI-induced neuropathic pain by regulating the P2X3 and the P2X7 expression on the ischiadic nerve.

Topics: Animals; Ganglia, Spinal; Gene Expression Regulation; Humans; Interleukin-1beta; Iridoids; Neuralgia; Nitric Oxide Synthase Type II; Pain Threshold; Rats; Receptors, Purinergic P2X3; Receptors, Purinergic P2X7; Sciatic Nerve; Tumor Necrosis Factor-alpha

Chronic hyperalgesia and allodynia associated with progressive damage of peripheral neurons are the most prevalent complications of diabetes mellitus. Plants belonging to the family of Oleaceae were traditionally used in folk medicine for the management of diabetes.. The aim of this study was to investigate whether an aqueous extract from the leaves of Ligustrum vulgare (common privet) could be useful to target neuropathic pain in a rat streptozotocin (STZ) model of diabetes.. The chemical composition of the aqueous extract from privet leaf was characterized with the UHPLC-DAD-MS method and the analytical quantification of its constituents was performed with HPLC-DAD. Mechanical hyperalgesia and allodynia were evaluated with the Randall-Selitto and von Frey tests.. Our investigation revealed the presence of secoiridoids: oleacein (23.48 ± 0.87 mg/g), oleocanthal (8.44 ± 0.08 mg/g), oleuropein (1.50 ± 0.01 mg/g), as well as phenylpropanoids: echinacoside (6.46 ± 0.07 mg/g), verbascoside (4.03 ± 0.04 mg/g) and p-coumaroyl glucarates in the dried aqueous extract of privet leaves. Behavioral data indicated that chronic intraperitoneal administration of the extract (50-200 mg/kg) for 21 days resulted in a decrease in diabetes-induced hyperalgesia and allodynia. Blood glucose levels remained unaltered, while body weight and water intake decreased significantly.. The aqueous privet leaf extract could serve useful in facilitating treatment of painful diabetic neuropathy. Additionally, the study showed that the antihyperalgesic activity of Ligustrum vulgare leaf extract is not likely related to its antihyperglycemic properties.

Topics: Aldehydes; Animals; Chromatography, High Pressure Liquid; Cyclopentane Monoterpenes; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Glucosides; Glycosides; Hyperalgesia; Iridoid Glucosides; Iridoids; Ligustrum; Male; Neuralgia; Phenols; Plant Extracts; Plant Leaves; Rats; Streptozocin