Complement Receptor C3aR1 Contributes to Paclitaxel-Induced Peripheral Neuropathic Pain in Mice and Rats.

Cancer chemotherapy-induced neuropathic pain is a devastating pain syndrome without effective therapies. We previously reported that rats deficient in complement C3, the central component of complement activation cascade, showed a reduced degree of paclitaxel-induced mechanical allodynia (PIMA), suggesting that complement is integrally involved in the pathogenesis of this model. However, the underlying mechanism was unclear. Complement activation leads to the production of C3a, which mediates inflammation through its receptor C3aR1. In this article, we report that the administration of paclitaxel induced a significantly higher expression level of C3aR1 on dorsal root ganglion (DRG) macrophages and expansion of these macrophages in DRGs in wild-type (WT) compared with in C3aR1 knockout (KO) mice. We also found that paclitaxel induced less severe PIMA, along with a reduced DRG expression of transient receptor potential channels of the vanilloid subtype 4 (TRPV4), an essential mediator for PIMA, in C3aR1 KO than in WT mice. Treating WT mice or rats with a C3aR1 antagonist markedly attenuated PIMA in association with downregulated DRG TRPV4 expression, reduced DRG macrophages expansion, suppressed DRG neuron hyperexcitability, and alleviated peripheral intraepidermal nerve fiber loss. Administration of C3aR1 antagonist to TRPV4 KO mice further protected them from PIMA. These results suggest that complement regulates PIMA development through C3aR1 to upregulate TRPV4 on DRG neurons and promote DRG macrophage expansion. Targeting C3aR1 could be a novel therapeutic approach to alleviate this debilitating pain syndrome.

Treatment of Refractory Low Back Pain Using Passive Recharge Burst in Patients Without Options for Corrective Surgery: Findings and Results From the DISTINCT Study, a Prospective Randomized Multicenter Controlled Trial.

OBJECTIVE: Spinal cord stimulation (SCS) is effective for relieving chronic intractable pain conditions. The Dorsal spInal cord STImulatioN vs mediCal management for the Treatment of low back pain study evaluates the effectiveness of SCS compared with conventional medical management (CMM) in the treatment of chronic low back pain in patients who had not undergone and were not candidates for lumbar spine surgery. METHODS AND MATERIALS: Patients were randomized to passive recharge burst therapy (n = 162) or CMM (n = 107). They reported severe pain and disability for more than a decade and had failed a multitude of therapies. Common diagnoses included degenerative disc disease, spondylosis, stenosis, and scoliosis-yet not to a degree amenable to surgery. The six-month primary end point compared responder rates, defined by a 50% reduction in pain. Hierarchical analyses of seven secondary end points were performed in the following order: composite responder rate (numerical rating scale [NRS] or Oswestry Disability Index [ODI]), NRS, ODI, Pain Catastrophizing Scale responder rate, Patient Global Impression of Change (PGIC) responder rate, and Patient-Reported Outcome Measure Information System-29 in pain interference and physical function. RESULTS: Intention-to-treat analysis showed a significant difference in pain responders on NRS between SCS (72.6%) and CMM (7.1%) arms (p < 0.0001). Of note, 85.2% of those who received six months of therapy responded on NRS compared with 6.2% of those with CMM (p < 0.0001). All secondary end points indicated the superiority of burst therapy over CMM. A composite measure on function or pain relief showed 91% of subjects with SCS improved, compared with 16% of subjects with CMM. A substantial improvement of 30 points was observed on ODI compared with a

A novel Diaphorobacter sp. strain isolated from saponification wastewater shows highly efficient phenanthrene degradation.

Polycyclic aromatic hydrocarbons (PAHs), such as phenanthrene, are a type of organic pollutants that exist widely in the environment. Of the currently known degradation methods, bioremediation is a desirable and feasible option. A novel Diaphorobacter sp. Strain MNS-0 was isolated from saponification wastewater and showed the ability to degrade phenanthrene, fluorene, acenaphthene, anthracene, benzo[a]anthracene, or chrysene using phenanthrene as the sole carbon source. Gas chromatography mass spectroscopy analysis of catabolic intermediates indicates that phenanthrene degradation occurs through the phthalic acid pathway in strain MNS-0. Genome sequencing shows that strain MNS-0 has two plasmids and one chromosome containing a presumptive phenanthrene degradation gene cluster. Strain MNS-0 was able to completely degrade 100 mg/L phenanthrene within 40 h and tolerate up to 10 g/L NaCl at pH 9.0, while maintaining phenanthrene degradation activity. We thus propose that strain MNS-0 is an effective degrader for bioremediation of PAHs pollution, even in relatively harsh alkali environments such as saponification wastewater.

Advances in Interventional Therapies for Painful Diabetic Neuropathy: A Systematic Review.

BACKGROUND: Painful diabetic neuropathy (PDN) is one of the major complications of diabetes mellitus. It is often debilitating and refractory to pharmaceutical therapies. Our goal was to systematically review and evaluate the strength of evidence of interventional management options for PDN and make evidence-based recommendations for clinical practice. METHODS: We searched PubMed, Scopus, Google Scholar, and Cochrane Llibrary and systematically reviewed all types of clinical studies on interventional management modalities for PDN. RESULTS: We identified and analyzed 10 relevant randomized clinical trials (RCTs), 8 systematic reviews/meta-analyses, and 5 observational studies of interventional modalities for PDN using pain as primary outcome. We assessed the risk of bias in grading of evidence and found that there is moderate to strong evidence to support the use of dorsal column spinal cord stimulation (SCS) in treating PDN in the lower extremities (evidence level: 1B+), while studies investigating its efficacy in the upper extremities are lacking. Evidence exists that acupuncture and injection of botulinum toxin-A provide relief in pain or muscle cramps due to PDN with minimal side effects (2B+/1B+). Similar level of evidence supports surgical decompression of lower limb peripheral nerves in patients with intractable PDN and superimposed nerve compression (2B±/1B+). Evidence for sympathetic blocks or neurolysis and dorsal root ganglion (DRG) stimulation is limited to case series (2C+). CONCLUSIONS: Moderate to strong evidence exists to support the use of SCS in managing lower extremity pain in patients who have failed conventional medical management for PDN. Acupuncture or injection of botulinum toxin-A can be considered as an adjunctive therapy for PDN. Surgical decompression of peripheral nerves may be considered in patients with PDN superimposed with nerve compression. High-quality studies are warranted to further evaluate the safety, efficacy, and cost-effectiveness of interventional therapies for PDN.

N-methyl-d-aspartate receptor subunit 2B on keratinocyte mediates peripheral and central sensitization in chronic post-ischemic pain in male rats.

The spinal N-methyl-d-aspartate (NMDA) receptor, and particularly its NR2B subunit, plays a pivotal role in neuropathic pain. However, the role of peripheral NMDA receptor in neuropathic pain is less well understood. We first treated cultured human keratinocytes, HaCaT cells with NMDA or NR2B-specific antagonist, ifenprodil and evaluated the level of total and phosphorylated NR2B at 24 h using Western blot. Next, using the chronic post-ischemia pain (CPIP) model, we administered NMDA or ifenprodil subcutaneously into the hind paws of male rats. Nociceptive behaviors were assessed by measuring mechanical and thermal withdrawal thresholds. Expression and phosphorylation of NR2B on keratinocyte were analyzed at 6, 12, 18, and 24 h on day 1 (initiation of pain) as well as day 2, 6, 10 and 14 (development and maintenance of pain) after the ischemia. The level of peripheral sensitization-related proteins (nuclear factor-κB (NF-κB), extracellular regulated protein kinases (ERK), and interleukin-1ß (IL-1ß)) in epidermis and dorsal root ganglion (DRG) were evaluated by immunofluorescence and western blot. Central sensitization-related C-fos induction, as well as astrocytes and microglia activation in the spinal cord dorsal horn (SDH) were studied using immunofluorescence. Administration of NMDA upregulated NR2B phosphorylation on HaCaT cells. CPIP-induced mechanical allodynia and thermal hyperalgesia were intensified by NMDA and alleviated by ifenprodil. CPIP resulted in an early upregulation of NR2B (peaked at 24 h) and late phosphorylation of NR2B (peaked at 14d) in hindpaw keratinocytes. CPIP led to an upregulation and phosphorylation of NF-κB and ERK, as well as an increased IL-1ß production in the ipsilateral skin and DRG. CPIP-associated c-fos induction in SDH persisted from acute to chronic stages after ischemia, while microglia and astrocyte activation were only observed in chronic phase. These CPIP-induced changes were also suppressed by ifenprodil administered subcutaneously in the hind paw. Our findings reveal a previously unrecognized role of keratinocyte NMDA receptor subunit 2B in peripheral and central nociceptive sensitization induced by CPIP.

Role of Complement in a Rat Model of Paclitaxel-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a painful and debilitating side effect of cancer chemotherapy with an unclear pathogenesis. Consequently, the available therapies for this neuropathic pain syndrome are inadequate, leading to a significantly reduced quality of life in many patients. Complement, a key component of the innate immune system, has been associated with neuroinflammation, a potentially important trigger of some types of neuropathic pain. However, the role of complement in CIPN remains unclear. To address this issue, we developed a C3 knockout (KO) rat model and induced CIPN in these KO rats and wild-type littermates via the i.p. administration of paclitaxel, a chemotherapeutic agent associated with CIPN. We then compared the severity of mechanical allodynia, complement activation, and intradermal nerve fiber loss between the groups. We found that 1) i.p. paclitaxel administration activated complement in wild-type rats, 2) paclitaxel-induced mechanical allodynia was significantly reduced in C3 KO rats, and 3) the paclitaxel-induced loss of intradermal nerve fibers was markedly attenuated in C3 KO rats. In in vitro studies, we found that paclitaxel-treated rat neuronal cells activated complement, leading to cellular injury. Our findings demonstrate a previously unknown but pivotal role of complement in CIPN and suggest that complement may be a new target for the development of novel therapeutics to manage this painful disease.

A Systematic Review of Growth Hormone in Pain Medicine: From Rodents to Humans.

OBJECTIVE: Growth hormone (GH) and GH-related signaling molecules play an important role in nociception and development of chronic pain. This review aims to examine the potential molecular mechanisms through which GH-related signaling modulates sensory hypersensitivity in rodents, the clinical pharmacology of GH, and the clinical evidence of GH treatment for several common pain syndromes. METHODS: A search was conducted using the PUBMED/MEDLINE database, Scopus, and the Cochrane library for all reports published in English on GH in pain management from inception through May 2018. A critical review was performed on the mechanisms of GH-related signaling and the pharmacology of GH. The levels of clinical evidence and implications for recommendations of all of the included studies were graded. RESULTS: The search yielded 379 articles, of which 201 articles were deemed irrelevant by reading the titles. There were 53 reports deemed relevant after reading abstracts. All of these 53 articles were retrieved for the analysis and discussion. CONCLUSIONS: Dysfunction of the GH/insulin-like growth factor 1 (IGF-1)/ghrelin axis was linked to hyperalgesia and several common clinical pain syndromes. Low levels of GH and IGF-1 were linked to pain hypersensitivity, whereas ghrelin appeared to provide analgesic effects. Pretreatment of GH reversed mechanical and thermal hypersensitivity in an animal model of inflammatory pain. Clinical trials support GH treatment in a subgroup of patients with fibromyalgia syndrome (level of evidence: 1B+) or chronic lower back pain syndrome (level of evidence: 2C+).

A metal-free and preconcentration-free method for non-enzymatic amperometric determination of pentachlorophenol using a ZIF-derived hollow carbon material.

An enzyme-free, metal-free, and preconcentration-free electrochemical sensor for pentachlorophenol assay has been fabricated. The interface of the sensor is based on a hollow zeolitic imidazolate framework-derived mesoporous carbon material (denoted as HZC/SPCE). The sensor exhibits linear amperometric response upon pentachlorophenol at 0.82 V (vs. Ag/AgCl) in the concentration range 0.001 to 26.8 mg L-1 (3.75 × 10-8~1.006 × 10-4 M) (R2 = 0.997). The sensitivity of HZC/SPCE is 3.53 × 102 µA mM-1 cm-2 with a detection limit of 2.05 × 10-9 M (S/N = 3) for pentachlorophenol. The method has been applied to the determination of pentachlorophenol in spiked food packaging samples with recoveries in the range 92.0 to 107.0%. Graphical abstract Schematic representation of the synthesis of hollow ZIFs-derived hollow carbon material. Free protons derived from tannic acid penetrated into ZIF-8 to destroy its solid framework and the outer parts covered by tannic acid were protected from further etching. After pyrolysis, the morphology of HZC remained similar to that of HZIF-8. Abbreviation: CTAB: hexadecyl trimethyl ammonium bromide; Melm: 2-methylimidazole; ZIF-8: zeolitic imidazolate framework-8; TA: tannic acid; HZIF-8: hollow zeolitic imidazolate framework-8; HZC: hollow zeolitic imidazolate frameworks (ZIFs)-derived mesoporous carbon material.

Intravenous Ketamine Infusion for Complex Regional Pain Syndrome: Survey, Consensus, and a Reference Protocol.

OBJECTIVE: To find and reach a consensus on the usage of ketamine in the treatment of complex regional pain syndrome and to determine a reference protocol for future studies. DESIGN: Three hundred fifty-one medical professionals participated in our survey on practice procedures, with 104 respondents providing information on their usage of ketamine for treating the pain associated with complex regional pain syndrome. Respondents answered questions about inpatient treatment, outpatient treatment, children vs adults, safety, and basic demographic information. An expert group then met to reach a consensus for a reference protocol. RESULTS: There is a difference in how inpatients are treated compared with outpatients, making it necessary to have two different reference protocols. The duration of pain relief varied from one to 10 days to one to six months, with a correlation between the duration of pain relief and total infusion hours per round. CONCLUSIONS: The consensus reference protocols are made up of nine recommended topics. Reference protocols need to be validated by extensive research before guidelines can be created.

The interactions of composting and biochar and their implications for soil amendment and pollution remediation: a review.

Compost and biochar, used for the remediation of soil, are seen as attractive waste management options for the increasing volume of organic wastes being produced. This paper reviews the interaction of biochar and composting and its implication for soil amendment and pollution remediation. The interaction of biochar and composting affect each other's properties. Biochar could change the physico-chemical properties, microorganisms, degradation, humification and gas emission of composting, such as the increase of nutrients, cation exchange capacity (CEC), organic matter and microbial activities. The composting could also change the physico-chemical properties and facial functional groups of biochar, such as the improvement of nutrients, CEC, functional groups and organic matter. These changes would potentially improve the efficiency of the biochar and composting for soil amendment and pollution remediation. Based on the above review, this paper also discusses the future research required in this field.

New advancements in spinal cord stimulation for chronic pain management.

PURPOSE OF REVIEW: To update the recent development of spinal cord stimulation (SCS) technology in the management of chronic pain. RECENT FINDINGS: Efficacy of SCS therapy has been significantly improved by the recent development of high frequency (HF-10 kHz) stimulation, burst stimulation, and dorsal root ganglion (DRG) stimulation. A few latest SCS modalities are in clinical trial. New approaches to guide lead placement and advances in surgical lead are introduced. SUMMARY: HF-10 SCS is free of paresthesia and associated with significantly better coverage of axial lower back pain. Burst stimulation invokes minimal paresthesia and provides better coverage of low back pain. DRG stimulation results in better outcomes in patients with complex regional pain syndrome. It requires less energy and delivers consistent stimulation regardless of postural variations. Clinical trials with new SCS modalities, such as Stimwaves, are under way to make SCS wireless. Intraoperative neuromonitoring and paresthesia atlas may be used to guide lead placement. Multicolumn surgical paddle leads enable a combination of independent current control with up to 32 contacts for better programming and better coverage.

Activation of cannabinoid receptor 2 attenuates mechanical allodynia and neuroinflammatory responses in a chronic post-ischemic pain model of complex regional pain syndrome type I in rats.

Complex regional pain syndrome type 1 (CRPS-I) remains one of the most clinically challenging neuropathic pain syndromes and its mechanism has not been fully characterized. Cannabinoid receptor 2 (CB2) has emerged as a promising target for treating different neuropathic pain syndromes. In neuropathic pain models, activated microglia expressing CB2 receptors are seen in the spinal cord. Chemokine fractalkine receptor (CX3CR1) plays a substantial role in microglial activation and neuroinflammation. We hypothesized that a CB2 agonist could modulate neuroinflammation and neuropathic pain in an ischemia model of CRPS by regulating CB2 and CX3CR1 signaling. We used chronic post-ischemia pain (CPIP) as a model of CRPS-I. Rats in the CPIP group exhibited significant hyperemia and edema of the ischemic hindpaw and spontaneous pain behaviors (hindpaw shaking and licking). Intraperitoneal administration of MDA7 (a selective CB2 agonist) attenuated mechanical allodynia induced by CPIP. MDA7 treatment was found to interfere with early events in the CRPS-I neuroinflammatory response by suppressing peripheral edema, spinal microglial activation and expression of CX3CR1 and CB2 receptors on the microglia in the spinal cord. MDA7 also mitigated the loss of intraepidermal nerve fibers induced by CPIP. Neuroprotective effects of MDA7 were blocked by a CB2 antagonist, AM630. Our findings suggest that MDA7, a novel CB2 agonist, may offer an innovative therapeutic approach for treating neuropathic symptoms and neuroinflammatory responses induced by CRPS-I in the setting of ischemia and reperfusion injury.

Intravenous Therapies for Complex Regional Pain Syndrome: A Systematic Review.

Complex regional pain syndrome (CRPS) remains a challenging clinical pain condition. Multidisciplinary approaches have been advocated for managing CRPS. Compared with spinal cord stimulation and intrathecal targeted therapy, IV treatments are less invasive and less costly. We aimed to systemically review the literature on IV therapies and determine the level of evidence to guide the management of CRPS. We searched PubMed, Embase, Scopus, and the Cochrane databases for articles published on IV therapies of CRPS up through February 2015. The search yielded 299 articles, of which 101 were deemed relevant by reading the titles and 63 by reading abstracts. All these 63 articles were retrieved for analysis and discussion. We evaluated the relevant studies and provided recommendations according to the level of evidence. We conclude that there is evidence to support the use of IV bisphosphonates, immunoglobulin, ketamine, or lidocaine as valuable interventions in selected patients with CRPS. However, high-quality studies are required to further evaluate the safety, efficacy, and cost-effectiveness of IV therapies for CRPS.

Responses of bacterial community and functional marker genes of nitrogen cycling to biochar, compost and combined amendments in soil.

Biochar and compost are seen as two attractive waste management options and are used for soil amendment and pollution remediation. The interaction between biochar and composting may improve the potential benefits of biochar and compost. We investigated soil physicochemical properties, bacterial community, bacterial 16S rRNA, and functional marker genes of nitrogen cycling of the soil remedied with nothing (S), compost (SC), biochar (SB), a mixture of compost and biochar (SBC), composted biochar (SBced), and a composted mixture of biochar and biomass (SBCing). The results were that all amendments (1) increased the bacterial community richness (except SB) and SBCing showed the greatest efficiency; (2) increased the bacterial community diversity (SBCing > SBC > SC > SBced > SB > S); and (3) changed the gene copy numbers of 16S rRNA, nirK, nirS, and nosZ genes of bacteria, ammonia-oxidizing archaea (AOA), and ammonia-oxidizing bacteria (AOB). All amendments (except SB) could increase the gene copy number of 16S rRNA, and SBCing had the greatest efficiency. The changes of soil bacterial community richness and diversity and the gene copy numbers of 16S rRNA, nirK, nirS, nosZ, AOA, and AOB would affect carbon and nitrogen cycling of the ecosystem and also implied that BCing had the greatest efficiency on soil amendment.

Intra-arterial therapy for acute ischemic stroke under general anesthesia versus monitored anesthesia care.

BACKGROUND: Recent studies have shown that intra-arterial recanalization therapy (IAT) for acute ischemic stroke (AIS) is associated with worse clinical outcomes when performed under general anesthesia (GA) compared to local anesthesia, with or without conscious sedation. The reasons for this association have not been systematically studied. METHODS: We retrospectively reviewed 190 patients who underwent IAT for anterior circulation AIS from January 2008 to December 2012 at our institution. Baseline demographics, vessels involved, acute stroke treatment including intravenous tissue type plasminogen activator (tPA) use, use of GA vs. monitored anesthesia care (MAC), location of thrombus, recanalization grade, radiologic post-procedural intracerebral hemorrhage, and 30-day outcomes were collected. Relevant clinical time points were recorded. Detailed intra-procedural hemodynamics including maximum/minimum heart rate, systolic blood pressure (BP), diastolic BP, mean BP, use of pressors and episodes of hypotension were collected. Our study's outcomes were as follows: in-hospital mortality, 30-day good outcome (mRS ≤2), successful recanalization and radiologic post-procedural intracerebral hemorrhage. RESULTS: Ninety-one patients received GA and 99 patients received MAC. There was no significant difference in the NIHSS score between the two groups but the GA group had a higher number of ICA occlusions (31.9 vs. 18.2%, p = 0.043). The time from the start of anesthesia to incision (23.0 ± 12.5 min vs. 18.7 ± 11.3 min, p = 0.020) and the time from the start of anesthesia to recanalization (110 ± 57.2 vs. 92.3 ± 43.0, p = 0.045) was longer in the GA group. The time from incision to recanalization was not significantly different between the two groups. mRS 0-2 was achieved in 22.8% of patients in the MAC group compared to 14.9% in GA (p = 0.293). Higher mortality was seen in the GA group (25.8 vs. 13.3%, p = 0.040). Successful recanalization (TICI 2b-3) was similar between the GA and MAC (57.8 vs. 48.5%, p = 0.182) groups, but GA had a higher number of parenchymal hematomas (26.3 vs. 10.1%, p = 0.003). There was no difference in the intra-procedural hemodynamic variables between the GA and MAC groups. Anesthesia type was an independent predictor for mortality (along with age and initial NIHSS), and the only independent predictor for parenchymal hematomas, with MAC being protective for both. CONCLUSION: Our study has confirmed previous findings of GA being associated with poorer outcomes and higher mortality in patients undergoing IAT for AIS. Detailed analysis of intra-procedural hemodynamics did not reveal any significant difference between the two groups. Parenchymal hematoma was the major driver of the difference in outcomes.

Efficacy and Safety of Pharmacological Treatment in Patients with Complex Regional Pain Syndrome: A Systematic Review and Meta-Analysis.

Complex regional pain syndrome (CRPS) is a disabling condition that usually affects the extremities after trauma or surgery. At present, there is no FDA-approved pharmacological treatment for patients with CRPS. We performed this systematic review and meta-analysis to evaluate the efficacy and safety of pharmacological therapies and determine the best strategy for CRPS. We searched the databases, including PubMed, Embase, Cochrane, Web of Science, Scopus, and ClinicalTrials.gov, for published eligible randomized controlled trials (RCTs) comparing pharmacological treatment with placebo in CRPS patients. Target patients were diagnosed with CRPS according to Budapest Criteria in 2012 or the 1994 consensus-based IASP CRPS criteria. Finally, 23 RCTs comprising 1029 patients were included. We used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to rate certainty (confidence in evidence and quality of evidence). Direct meta-analysis showed that using bisphosphonates (BPs) (mean difference [MD] -2.21, 95% CI -4.36--0.06, p = 0.04, moderate certainty) or ketamine (mean difference [MD] -0.78, 95% CI -1.51--0.05, p = 0.04, low certainty) could provide long-term (beyond one month) pain relief. However, there was no statistically significant difference in the efficacy of short-term pain relief. Ketamine (rank p = 0.55) and BPs (rank p = 0.61) appeared to be the best strategies for CRPS pain relief. Additionally, BPs (risk ratio [RR] = 1.86, 95% CI 1.34-2.57, p < 0.01, moderate certainty) and ketamine (risk ratio [RR] = 3.45, 95% CI 1.79-6.65, p < 0.01, moderate certainty) caused more adverse events, which were mild, and no special intervention was required. In summary, among pharmacological interventions, ketamine and bisphosphonate injection seemed to be the best treatment for CRPS without severe adverse events.

NMDA Receptors Regulate Oxidative Damage in Keratinocytes during Complex Regional Pain Syndrome in HaCaT Cells and Male Rats.

Complex regional pain syndrome (CRPS), a type of primary chronic pain, occurs following trauma or systemic disease and typically affects the limbs. CRPS-induced pain responses result in vascular, cutaneous, and autonomic nerve alterations, seriously impacting the quality of life of affected individuals. We previously identified the involvement of keratinocyte N-methyl-d-asparagic acid (NMDA) receptor subunit 2 B (NR2B) in both peripheral and central sensitizations in CRPS, although the mechanisms whereby NR2B functions following activation remain unclear. Using an in vivo male rat model of chronic post-ischemia pain (CPIP) and an in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) cell model, we discovered that oxidative injury occurs in rat keratinocytes and HaCaT cells, resulting in reduced cell viability, mitochondrial damage, oxidative damage of nucleotides, and increased apoptosis. In HaCaT cells, OGD/R induced increases in intracellular reactive oxygen species levels and disrupted the balance between oxidation and antioxidation by regulating a series of antioxidant genes. The activation of NMDA receptors via NMDA exacerbated these changes, whereas the inhibition of the NR2B subunit alleviated them. Co-administration of ifenprodil (an NR2B antagonist) and NMDA (an NMDA receptor agonist) during the reoxygenation stage did not result in any significant alterations. Furthermore, intraplantar injection of ifenprodil effectively reversed the altered gene expression that was observed in male CPIP rats, thereby revealing the potential mechanisms underlying the therapeutic effects of peripheral ifenprodil administration in CRPS. Collectively, our findings indicate that keratinocytes undergo oxidative injury in CRPS, with NMDA receptors playing regulatory roles.

Blockade of Type 2A Protein Phosphatase Signaling Attenuates Complement C1q-Mediated Microglial Phagocytosis of Glutamatergic Synapses Induced by Amyloid Fibrils.

We previously reported the critical involvement of metabotropic GluR1 (mGluR1) signaling in complement C1q-dependent microglial phagocytosis of glutamatergic synapses in a rat model of Alzheimer's disease (AD) injected with amyloid fibrils. Here, we explored the role of type 2A protein phosphatase (type 2A PPase), a key enzyme downstream of mGluR1 signaling, in the pathogenesis of AD in rats. Significant local upregulation of PP2A expression was observed in the hippocampal CA1 after bilateral microinjection of amyloid-beta (Aß1-40) fibrils. Amyloid fibrils induced remarkable dephosphorylation of pFMRP (fragile X mental retardation protein) and C1q upregulation in hippocampal glutamatergic synapses, which was ameliorated by microinjection of type 2A PPase inhibitor okadaic acid (OA). Microinjection of OA further attenuated the microglial phagocytosis of glutamatergic synapses, recovered the hippocampal glutamatergic transmission, and improved the performance in Morris water maze test. These findings demonstrated that dysfunction of type 2A PPase signaling contributed to complement C1q-dependent microglial phagocytosis of glutamatergic synapses and the cognitive impairments in the rat model of AD.

The Role of Neuroinflammation in Complex Regional Pain Syndrome: A Comprehensive Review.

Complex Regional Pain Syndrome (CRPS) is an excess and/or prolonged pain and inflammation condition that follows an injury to a limb. The pathogenesis of CRPS is multifaceted that remains incompletely understood. Neuroinflammation is an inflammatory response in the peripheral and central nervous systems. Dysregulated neuroinflammation plays a crucial role in the initiation and maintenance of pain and nociceptive neuronal sensitization, which may contribute to the transition from acute to chronic pain and the perpetuation of chronic pain in CRPS. The key features of neuroinflammation encompass infiltration and activation of inflammatory cells and the production of inflammatory mediators in both the central and peripheral nervous systems. This article reviews the role of neuroinflammation in the onset and progression of CRPS from six perspectives: neurogenic inflammation, neuropeptides, glial cells, immune cells, cytokines, and keratinocytes. The objective is to provide insights that can inform future research and development of therapeutic targets for CRPS.