VGLUT2/Cdk5/p25 Signaling Pathway Contributed to Inflammatory Pain by Complete Freund's Adjuvant.

Vesicular glutamate transporter type 2 (VGLUT2) is known to play an important role in mediating heat hyperalgesia induced by inflammation. However, the underlying mechanism for this activity is poorly understood. Cyclin-dependent kinase 5 (Cdk5), serving as a key regulator in modulating release of glutamate, acted a key player in the formation of heat hyperalgesia of inflammatory pain. However, it remains unknown whether there is a bridge between Cdk5 and VGLUT2 for mediating inflammatory pain. Therefore, we designed the experiment to determine whether VGLUT2 signaling pathway is involved in inflammatory pain mediated by Cdk5 in the inflammatory pain model induced by complete Freund's adjuvant (CFA). Our results showed that the coexpression of Cdk5/VGLUT2 in small- and medium-sized neuronal cells of the dorsal root ganglion (DRG) and spinal cord between days 1 and 3 following subcutaneous injection of CFA was significantly increased. Moreover, our study revealed that the expression of VGLUT2 protein in the DRG and spinal cord was remarkably increased between days 1 and 3 following CFA injection and was significantly reduced by roscovitine, a selective antagonist of Cdk5. Additionally, p25 but not p35, an activator of Cdk5, protein was significantly increased by CFA and reduced by roscovitine. Our findings suggested that VGLUT2/Cdk5 signaling pathway contributes to inflammatory pain mediated by Cdk5/p25.

Relation of postoperative serum S100A12 levels to delirium and cognitive dysfunction occurring after hip fracture surgery in elderly patients.

OBJECTIVE: Brain injury is implicated in pathogenesis of postoperative delirium (POD) and cognitive dysfunction (POCD). S100A12 is involved in inflammatory process and is recently known as a biomarker for brain injury. Herein, we clarified whether serum S100A12 levels are related to POD and POCD after hip fracture surgery in elderly patients. MATERIALS AND METHODS: In this prospective, observational study, we gauged S100A12 levels in preoperative and postoperative serum from 186 patients and serum from 186 controls. Patients were categorized according to the presence of POD and POCD. RESULTS: Postoperative, but not preoperative serum S100A12 levels were significantly higher in patients than in controls. There was a positive and independent correlation between postoperative C-reactive protein and S100A12 levels (t = 8.797, p < 0.001). Postoperative S10012 levels and age were independently associated with the risk of developing POD (S100A12 levels: odds ratio [OR] = 1.166, 95% confidence interval [CI] = 1.045-2.087, p = 0.001; age: OR = 1.243, 95% CI = 1.073-1.419, p = 0.012) and POCD (S100A12: OR = 1.157, 95% CI = 1.030-1.986, p = 0.003; age: OR = 1.228, 95% CI = 1.054-1.387, p = 0.014). In terms of area under receiver operating characteristic curve, postoperative S100A12 levels had a higher predictive ability than age and their combination dramatically exceeded that of each one alone. CONCLUSIONS: Postoperative elevated serum S100A12 levels have a strong relation to inflammation and are associated independently with the development of POD and POCD, substantializing serum S100A12 as a potential biomarker for predicting POD and POCD in elderly patients undergoing hip fracture surgery.

Synovial fluid concentrations of cold-inducible RNA-binding protein are associated with severity in knee osteoarthritis.

BACKGROUND: Cold-inducible RNA-binding protein (CIRP) is a pro-inflammatory cytokine. We determined whether serum or synovial fluid concentrations are associated with severity in osteoarthritis (OA). METHODS: CIRP concentrations in serum and synovial fluid from 156 knee OA patients and serum from 156 controls were determined. The Kellgren and Lawrence (KL) grade, Lequesne index and Western Ontario McMaster University Osteoarthritis Index (WOMAC) pain score were used to assess radiographic, clinical severity and pain severity respectively. Their scores were dichotomized based on their median values. RESULTS: OA patients had similar serum CIRP concentrations compared to controls. In OA patients, CIRP concentrations in synovial fluid were dramatically higher compared to, but not correlated with paired serum samples. CIRP concentrations in synovial fluid were significantly correlated with synovial fluid or serum C-reactive protein, tumor necrosis factor- alpha and interleukin-6 concentrations, KL grade, Lequesne index and WOMAC pain score. Synovial fluid CIRP concentrations were independently related to the KL grade>2, Lequesne index >13 and WOMAC pain score>12. Under receiver operating characteristic curves, Synovial fluid CIRP concentrations significantly predicted them. CONCLUSIONS: Increased synovial fluid CIRP concentrations were closely associated with the severity, substantializing CIRP as a potential marker for synovial inflammation of OA.

Intrathecal SRT1720, a SIRT1 agonist, exerts anti-hyperalgesic and anti-inflammatory effects on chronic constriction injury-induced neuropathic pain in rats.

Neuropathic pain is caused by lesion or inflammation of the nervous system and characterized by the symptoms of allodynia, hyperalgesia and spontaneous pain. SIRT1 (Sir2) is a NAD-dependent deacetylase and is reported to regulate a wide variety of cellular processes including inflammation, aging and lifespan extension. Nevertheless, the role of SIRT1 in neuropathic pain is not fully understood. The present study was intended to detect the effect of intrathecal SRT1720, a SIRT1 agonist, using quantitative real-time PCR and western blot analysis over time in rats following chronic constriction injury (CCI) or sham surgery. In addition, the effect of intrathecal injection of SRT1720 on thermal hyperalgesia and mechanical allodynia was evaluated in CCI rats. It was found that daily intrathecal injection of SRT1720 before and 1, 3, 5, 7 days after CCI surgery produced a transient inhibitory effect on thermal hyperalgesia and mechanical allodynia in CCI rats. In addition, an intrathecal injection of STR1-siRNA before SRT1720 administration reversed the anti-nociceptive effect of SRT1720. Furthermore, intrathecal injection of SRT1720 significantly down-regulated the expression of mammalian target of rapamycin (mROT), NF-κB and inflammatory cytokines, such as IL-6, TNF-α and iNOS mRNA. These data indicate that intrathecal SRT1720 may be an alternative strategy for the treatment of neuropathic pain. Our findings suggest that intrathecal SRT1720, a SIRT1 agonist, exerts antihyperalgesic and antiinflammatory effects on CCI-induced neuropathic pain in rats.