Gastrodia elata Blume Polysaccharides Attenuate Vincristine-Evoked Neuropathic Pain through the Inhibition of Neuroinflammation.

Vincristine (Vin) is a well-known antitumor agent that frequently evokes neuropathic pain and decreases the quality of life of patients. Polysaccharides (GBP) extracted from Gastrodia elata Blume have been demonstrated to possess anti-inflammatory and neuroprotective effects in vivo; however, the effects of GBP on Vin-induced neuropathic pain remain unknown. The present study is aimed at exploring the alleviative potential of GBP against chemotherapy-evoked peripheral neuropathy to better understand and extend its pharmacological application. Vin was administered intraperitoneally to evoke neuropathic pain. GBP was orally administered for 21 days. The mechanical allodynia and thermal hyperalgesia were assessed using the Von Frey test and hot-plate test. Histopathological changes were assessed by hematoxylin and eosin staining. ELISA kits were used to measure the levels of inflammatory cytokines in the sciatic nerve, spinal cord, and dorsal root ganglion (DRG). qRT-PCR was employed to examine the expression of inflammatory cytokines and Sirtuin1 (SIRT1) in the sciatic nerve, spinal cord, and DRG. Our findings revealed that GBP treatment enhanced the paw withdrawal latency and paw withdrawal threshold and restored Vin-induced sciatic nerve damage in rats. GBP also attenuated the Vin-induced increase of proinflammatory cytokine levels, including IL-6, IL-8, TNF-α, IL-1ß, and NF-κB. On the molecular level, treatment with GBP downregulated the mRNA levels of IL-6, IL-8, TNF-α, and IL-1ß in the sciatic nerve, spinal cord, and DRG. Meanwhile, GBP increased SIRT1 activity and mRNA expression levels. Our data indicated that GBP exerted a potential protective effect against chemotherapy-induced neuropathic pain which might be mediated via the inhibition of neuroinflammation.

Role of Sigma-1 Receptor/p38 MAPK Inhibition in Acupoint Catgut Embedding-Mediated Analgesic Effects in Complete Freund's Adjuvant-Induced Inflammatory Pain.

BACKGROUND: The endoplasmic reticulum chaperone protein Sigma-1 receptor (Sig-1 R) and mitogen-activated protein kinases (MAPKs) are involved in the mechanism of pain. Acupoint stimulation exerts an exact antihyperalgesic effect in inflammatory pain. However, whether Sig-1 R and MAPKs are associated with the acupoint stimulation-induced analgesic effects is not clear. This study investigated the analgesic effect of acupoint catgut embedding (ACE) and the inhibition of Sig-1 R and MAPKs in ACE analgesia. METHODS: Rats were prepared with intrathecal catheter implantation. ACE was applied to bilateral "Kunlun" (BL60), "Zusanli" (ST36), and "Sanyinjiao" (SP6) acupoints in the rat model of inflammatory pain (complete Freund's adjuvant [CFA] intraplantar injection). Then, Sig-1R agonist PRE084 or saline was intrathecally given daily. The paw withdrawal thresholds and paw edema were measured before CFA injection and at 1, 3, and 5 day after CFA injection. Western bolt was used to evaluate the protein expression of spinal Sig-1R, p38MAPK, and extracellular signal-regulated kinase (ERK), and immunohistochemistry of Sig-1R was detected at 1, 3, and 5 days after CFA injection. RESULTS: ACE exhibited specific analgesic effects. ACE increased paw withdrawal thresholds and markedly decreased CFA-induced paw edema at 1, 3, and 5 days. ACE downregulated the protein expression of Sig-1R, which was increased significantly at 1, 3, and 5 days after CFA injection. ACE decreased the expression of p38 MAPK and ERK at 1 and 3 days but not at 5 days. However, an injection of Sig-1R agonist PRE084 markedly reversed these alterations, except ERK expression. CONCLUSIONS: The present study demonstrated that ACE exhibited antihyperalgesic effects via the inhibition of the Sig-1R that modulated p38 MAPK, but not ERK, expression in the CFA-induced inflammatory pain model in rats.

Pregabalin-induced delayed cutaneous hypersensitivity reaction occurring after 40 days of use: a case report.

Pregabalin is the first-line treatment for neuropathic pain. Cases of cutaneous hypersensitivity reactions caused by pregabalin generally occur within 2 weeks of initiating medication. We report a rare case of a delayed cutaneous hypersensitivity reaction caused by pregabalin, which was confirmed by a drug provocation test. A 72-year-old man with severe herpes zoster neuralgia developed maculopapular drug eruption covering 80% to 90% of his total body surface area after 40 days of combined multidrug analgesia. A drug provocation test for pregabalin was positive. The time interval between initiating medication and the onset of the patient's rash was the longest and he also had the largest area of skin affected compared with patients with a similar condition in previous related reports. Remaining vigilant for possible adverse cutaneous hypersensitivity reactions during treatment is important because of the long-term course of pregabalin treatment for neuropathic pain.

Effect of inspiratory muscle training on hypoxemia in obese patients undergoing painless gastroscopy: protocol for a single-center, double-blind, randomized controlled trial.

Introduction: Obese patients who undergo painless gastroscopy are particularly prone to suffer from upper airway obstruction, respiratory depression, and subsequent hypoxemia. Despite adequate preoxygenation, the incidence of hypoxemia remains high. Recently, inspiratory muscle training (IMT) has been considered to be a promising strategy to increase respiratory muscle strength and endurance with the attendant improvement of pulmonary function. However, it remains unclear whether IMT is associated with a lower rate of hypoxemia in obese patients during this sedative procedure. This study aims to investigate the effectiveness of IMT used in obese patients who are scheduled for selective painless gastroscopy. Methods and analysis: This prospective, randomized controlled trial (RCT) will enroll 232 obese patients with a body mass index (BMI) of 35-39.9 kg·m-2 who undergo painless gastroscopy at the First Affiliated Hospital of Xiamen University. Subjects will be randomly assigned to two groups with a 1:1 ratio. Participants in both groups will receive IMT for 4 weeks prior to gastroscopy. The intervention group will receive IMT with a load of 30% of the maximal inspiratory pressure (Pi(max)) in the first week, with an increase of 10% per week since the following week, while the counterparts in the control group will not receive any load during the 4-week IMT. The primary outcome is the incidence of hypoxemia during painless gastroscopy. Secondary outcomes include the need for airway maneuvers, blood pressure changes, sleep quality assessment, pro-inflammatory cytokines levels, and monitoring of adverse events. Discussions: The outcomes of this study will offer invaluable guidance for the clinical implementation of IMT as a potential non-invasive preventive measure. Additionally, it stands to enrich our comprehension of anesthesia management and airway-related challenges in obese patients undergoing procedural sedation, which we anticipate will further contribute to addressing the turnaround concerns within high-volume, swiftly paced ambulatory endoscopy centers. Ethics and dissemination: This study has been approved by the Ethics Committee of the First Affiliated Hospital of Xiamen University (2022, No.091). The results will be submitted for publication in peer-reviewed journals. Trial registration number: China Clinical Trial Center (ChiCTR2200067041).

To Inadvertent Vascular Placement of an Intrathecal Catheter: A Case Report.

Intrathecal drug delivery systems (IDDS) are a treatment option for patients with chronic nonmalignant pain and cancer pain. In this case report, we describe a patient in whom an intrathecal catheter was implanted into a blood vessel rather than into the subarachnoid cavity. A contrast agent was administered, and digital subtraction angiography (DSA) imaging suggested that the catheter was inserted into a blood vessel. The anterior spinal arteries and veins were verified on the ventral side of the spinal cord without interruption. To our knowledge, this is the first report of implantation of an IDDS catheter into a blood vessel.

Puerarin Attenuates Complete Freund's Adjuvant-Induced Trigeminal Neuralgia and Inflammation in a Mouse Model via Sirt1-Mediated TGF-ß1/Smad3 Inhibition.

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, anti­inflammatory, 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-1ß (IL-1ß; 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-1ß/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-ß1 (TGF-ß1) 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-ß1/Smad3 activity. The pharmacological activity of Pue provides a new perspective for the effective prevention and treatment of TN.

Puerarin alleviates vincristine-induced neuropathic pain and neuroinflammation via inhibition of nuclear factor-κB and activation of the TGF-ß/Smad pathway in rats.

Chemotherapy-induced neuropathic pain harms the quality of life patients. Vincristine is an often used chemotherapeutic drug that evokes neuralgia via inflammation. Puerarin (Pue) extracted from Puerariae Lobatae Radix has analgesic and anti-inflammatory effects; however, its possible effect and mechanism in vincristine (Vin)-induced neuropathic pain has not been investigated. The present research aimed to explore whether Pue could relieve chemotherapy-evoked neuropathic pain and the underlying mechanism actions. Rat neuropathic pain was established by intraperitoneal injection of vincristine. Pue was orally administered in two dose levels (25 or 50 mg/kg/d) for three weeks. The paw withdrawal latency and paw withdrawal threshold were performed to evaluate the pain behaviors. Inflammatory cytokines in the spinal cord and dorsal root ganglion were measured by ELISA kits. qRT-PCR, western blot, and immunofluorescence staining were employed to measure the level and expression feature of inflammatory cytokines. Our findings showed that Pue improved hyperalgesia and allodynia. Treatment with Pue restored the levels of tumor necrosis factor-α (TNF-α), and IL-1ß and increased the levels of transforming growth factor-ß (TGF-ß), and interleukin-10 (IL-10). On the molecular level, treatment with Pue down-regulated the protein levels of IL-1ß, and NF-κBp65 and up-regulated the protein levels of TGF-ß, p-Smad2, and p-Smad3 (TGF-ß/Smad) in the spinal cord and DRG. Immunofluorescence staining further demonstrated that Pue decreased the NF-κBp65 protein. Our findings imply that Pue relieved chemotherapy-induced neuropathic pain might be attributable to the suppression of inflammation cytokines. The anti-inflammation action of Pue might be associated with the activation of the TGF-ß/Smad pathway, a novel mechanism exploring its prophylactic effect in vincristine-induced neuropathic pain.

Electroacupuncture brain protection during ischemic stroke: A role for the parasympathetic nervous system.

The demand for using parasympathetic activation for stroke therapy is unmet. In the current study, we investigated whether the neuroprotection provided by electroacupuncture (EA) in an experimental stroke model was associated with activation of the parasympathetic nervous system (PNS). The results showed that parasympathetic dysfunction (PD), performed as unilateral vagotomy combined with peripheral atropine, attenuated both the functional benefits of EA and its effects in improving cerebral perfusion, reducing infarct volume, and hindering apoptosis, neuronal and peripheral inflammation, and oxidative stress. Most importantly, EA rats showed a dramatically less reduction in the mRNA level of choline acetyltransferase, five subtypes of muscarinic receptors and α7nAChR, suggesting the inhibition of the impairment of the central cholinergic system; EA also activated dorsal motor nucleus of the vagus, the largest source of parasympathetic pre-ganglionic neurons in the lower brainstem (detected by c-fos immunohistochemistry), and PD suppressed these changes. These findings indicated EA may serve as an alternative modality of PNS activation for stroke therapy.