Syringaresinol Alleviates Oxaliplatin-Induced Neuropathic Pain Symptoms by Inhibiting the Inflammatory Responses of Spinal Microglia

Oxaliplatin-induced peripheral neuropathy (OIPN) is a serious side effect that impairs the quality of life of patients treated with the chemotherapeutic agent, oxaliplatin. The underlying pathophysiology of OIPN remains unclear, and there are no effective therapeutics. This study aimed to investigate the causal relationship between spinal microglial activation and OIPN and explore the analgesic effects of syringaresinol, a phytochemical from the bark of Cinnamomum cassia, on OIPN symptoms. The causality between microglial activation and OIPN was investigated by assessing cold and mechanical allodynia in mice after intrathecal injection of the serum supernatant from a BV-2 microglial cell line treated with oxaliplatin. The microglial inflammatory response was measured based on inducible nitric oxide synthase (iNOS), phosphorylated extracellular signal-regulated kinase (p-ERK), and phosphorylated nuclear factor-kappa B (p-NF-κB) expression in the spinal dorsal horn. The effects of syringaresinol were tested using behavioral and immunohistochemical assays. We found that oxaliplatin treatment activated the microglia to increase inflammatory responses, leading to the induction of pain. Syringaresinol treatment significantly ameliorated oxaliplatin-induced pain and suppressed microglial expression of inflammatory signaling molecules. Thus, we concluded that the analgesic effects of syringaresinol on OIPN were achieved via the modulation of spinal microglial inflammatory responses.     

Reduced Endocannabinoid Tone in Saliva of Chronic Orofacial Pain Patients

Background: the endocannabinoid system (ECS) participates in many physiological and pathological processes including pain generation, modulation, and sensation. Its involvement in chronic orofacial pain (OFP) in general, and the reflection of its involvement in OFP in salivary endocannabinoid (eCBs) levels in particular, has not been examined. Objectives: to evaluate the association between salivary (eCBs) levels and chronic OFP. Methods: salivary levels of 2 eCBs, anandamide (AEA), 2-arachidonoylglycerol (2-AG), 2 endocannabinoid-like compoundsN-palmitoylethanolamine (PEA), N-oleoylethanolamine (OEA), and their endogenous precursor and breakdown product, arachidonic acid (AA), were analyzed using liquid chromatography/tandem mass spectrometry in 83 chronic OFP patients and 43 pain-free controls. The chronic OFP patients were divided according to diagnosis into musculoskeletal, neurovascular/migraine, and neuropathic pain types. Results: chronic OFP patients had lower levels of OEA (p = 0.02) and 2-AG (p = 0.01). Analyzing specific pain types revealed lower levels of AEA and OEA in the neurovascular group (p = 0.04, 0.02, respectively), and 2-AG in the neuropathic group compared to controls (p = 0.05). No significant differences were found between the musculoskeletal pain group and controls. Higher pain intensity was accompanied by lower levels of AA (p = 0.028), in neuropathic group. Conclusions: lower levels of eCBs were found in the saliva of chronic OFP patients compared to controls, specifically those with neurovascular/migraine, and neuropathic pain. The detection of changes in salivary endocannabinoids levels related to OFP adds a new dimension to our understanding of OFP mechanisms, and may have diagnostic as well as therapeutic implications for pain.     

MRI参数对腰椎间盘突出症患者椎间盘退变程度的评估价值及与JOA、VAS评分相关性

选择腰椎间盘突出症(LDH)患者60例,分为轻度退变组、中度退变组、重度退变组.患者均行MRI检查,比较3组的MRI参数,包括髓核(NP)区、纤维环(AF)区T2值.检测比较发现,3组LDH患者NP区、AF区T2值间存在明显差异,且与腰椎功能评分(JOA)呈正相关,与腰部疼痛评分(VAS)呈负相关(P＜0.05).NP...     

The Microglial Activation Inhibitor Minocycline,Used Alone and in Combination with Duloxetine,Attenuates Pain Caused by Oxaliplatin in Mice

The antitumor drug, oxaliplatin, induces neuropathic pain, which is resistant to available analgesics, and novel mechanism-based therapies are being evaluated for this debilitating condition. Since activated microglia, impaired serotonergic and noradrenergic neurotransmission and overexpressed sodium channels are implicated in oxaliplatin-induced pain, this in vivo study assessed the effect of minocycline, a microglial activation inhibitor used alone or in combination with ambroxol, a sodium channel blocker, or duloxetine, a serotonin and noradrenaline reuptake inhibitor, on oxaliplatin-induced tactile allodynia and cold hyperalgesia. To induce neuropathic pain, a single dose (10 mg/kg) of intraperitoneal oxaliplatin was used. The mechanical and cold pain thresholds were assessed using mouse von Frey and cold plate tests, respectively. On the day of oxaliplatin administration, only duloxetine (30 mg/kg) and minocycline (100 mg/kg) used alone attenuated both tactile allodynia and cold hyperalgesia 1 h and 6 h after administration. Minocycline (50 mg/kg), duloxetine (10 mg/kg) and combined minocycline + duloxetine influenced only tactile allodynia. Seven days after oxaliplatin, tactile allodynia (but not cold hyperalgesia) was attenuated by minocycline (100 mg/kg), duloxetine (30 mg/kg) and combined minocycline and duloxetine. These results indicate a potential usefulness of minocycline used alone or combination with duloxetine in the treatment of oxaliplatin-induced pain.     

In Vitro Cytotoxic Protective Effect of Alginate-Encapsulated Capsaicin Might Improve Skin Side Effects Associated with the Topical Application of Capsaicin

Chronic neuropathic pain, particularly peripheral pain, is a cause of great concern for diabetic patients. Current treatments include numerous agents such as capsaicinoids, a known deterrent of neuropathic pain despite the inconvenience associated with local side effects. In this context, the current work aims to elucidate the potential mechanisms involved in cytotoxicity by capsaicin and proposes an efficient formulation of capsaicin in alginate microcapsules, which significantly reduces side effects from capsaicin topical administration. For this, human dermal fibroblast cells were treated with alginate-microencapsulated capsaicin extracts and screened for potential cytotoxic effects produced by the treatment. Cell viability and morphology were examined, as well as oxidative stress status and anti-inflammatory potential. Our results show that the alginate encapsulated formulation of capsaicin exerted lower cytotoxic effects on human dermal fibroblasts as measured by cell viability and reactive oxygen species (ROS) production. Furthermore, the expression profiles of inflammatory cytokines were significantly altered by the treatment as compared with the control culture.     

Inhibition of Thiol-Mediated Uptake with Irreversible Covalent Inhibitors

Thiol-mediated uptake is emerging as method of choice to penetrate cells. This study focuses on irreversible covalent inhibitors of thiol-mediated uptake. High-content high-throughput screening of the so far largest collection of hypervalent iodine reagents affords inhibitors that are more than 250 times more active than Ellman’s reagent and rival the best dynamic covalent inhibitors. Comparison with other irreversible reagents reveals that inhibition within one series follows reactivity, whereas inhibition across series deviates from reactivity. These trends support that molecular recognition, besides dynamic covalent exchange, contributes significantly to thiol-mediated uptake. The most powerful inhibitors besides the best hypervalent iodine reagents were Fukuyama’s nosyl protecting group and super-cinnamaldehydes that have been introduced as irreversible activators of the pain receptor TRPA1. Considering that several viruses use different forms of thiol-mediated uptake to enter cells, the identification of new irreversible inhibitors of thiol-mediated uptake is of general interest for the discovery of new antivirals.     

Synthesis and Structure–Activity Relationship Studies of Benzimidazole-4,7-dione-Based P2X3 Receptor Antagonists as Novel Anti-Nociceptive Agents

P2X3 receptors (P2X3R) are ATP-gated ion channels predominantly expressed in C- and Aδ-fiber primary afferent neurons and have been introduced as a novel therapeutic target for neurological disorders, including neuropathic pain and chronic cough. Because of its localized distribution, antagonism of P2X3R has been thoroughly considered, and the avoidance of issues related to CNS side effects has been proven in clinical trials. In this article, benzimidazole-4,7-dione-based derivatives were introduced as a new chemical entity for the development of P2X3R antagonists. Starting from the discovery of a hit compound from the screening of 8364 random library compounds in the Korea Chemical Bank, which had an IC₅₀ value of 1030 nM, studies of structure–activity and structure–property relationships enabled further optimization toward improving the antagonistic activities as well as the drug’s physicochemical properties, including metabolic stability. As for the results, the final optimized compound 14h was developed with an IC₅₀ value of 375 nM at P2X3R with more than 23-fold selectivity versus P2X2/3R, along with properties of metabolic stability and improved solubility. In neuropathic pain animal models evoked by either nerve ligation or chemotherapeutics in male Sprague-Dawley rats, compound 14h showed anti-nociceptive effects through an increase in the mechanical withdrawal threshold as measured by von Frey filament following intravenous administration.     

两种药物膀胱灌注治疗间质性膀胱炎的临床疗效观察

目的 观察并比较透明质酸钠、碱化利多卡因联合肝素膀胱灌注治疗膀胱疼痛综合征/ 间质性膀胱炎（BPS/IC）的临 床疗效。方法 将63 例BPS/IC 患者按随机单盲的原则分成A、B 两组,A 组32 例,B 组31 例。A 组患者予膀胱灌注透明质酸钠40ml;B 组予膀胱灌注碱化利多卡因联合肝素治疗,即用5%碳酸氢钠10ml、2%利多卡因10ml、肝素钠2.5 万U 和0.9%氯化钠15ml的混合液行膀胱灌注。两组均保留40~60min,每周2 次,4周后改为每周1 次,共16 次。观察两组患者用药前及用药开始后4、12周时的O’Leary-Sant平均症状评分（ICPI）、问题评分（ICSI）及生活质量评分（QOL）,并记录不良反应。结果 两组患者治疗开始后4周和12 周ICPI、ICSI 及QOL评分均有明显改善,与治疗前比较均有统计学差异（均P＜0.05）。治疗4 周后两组的ICPI、ICSI 及QOL 评分下降分值比较均无统计学差异（均P＞0.05）,但治疗12 周后A 组的ICPI、ICSI 及QOL评分下降分值较B 组更为明显（均P＜0.05）。所有患者治疗过程中均未发生明显不良反应。结论 透明质酸钠及碱化利多卡因联合肝素膀胱灌注均能改善BPS/IC患者的临床症状,而透明质酸钠疗效更为显著。     

一站式CT检查系统在急性胸痛患者干预方案中的应用

本研究探讨一站式CT检查系统在急性胸痛患者管理中干预方案的应用。将符合急性胸痛患者49例纳入研究,采用自动触发方式采集患者上胸部volume数据集和心胸部volume数据集,经过处理后获得胸主动脉、冠状动脉、肺动脉及全胸部图像。本研究中,测量结果发现平均CT值主动脉弓是(332±51)Hu,升主动脉是(435±53)Hu,肺动脉干是(491±93)Hu,降主动脉是(454±70)Hu,而左冠状动脉和右冠状动脉分别是(425±60)Hu、(415±62)Hu。病变鉴定发现,急性肺栓塞12例,主动脉弓动脉粥样硬化斑块破裂8例,肺组织实变4例,慢性肺栓塞伴右心衰竭2例,胸腔积液2例,左冠状动脉非关键性狭窄11例,右冠状动脉非关键性狭窄7例,心包积液2例,复合解剖畸形1例。总之,本研究通过一站式CT检查系统对急性胸痛患者干预方案的制定提供了重要指导。