Therapeutic potential for leukocyte elastase in chronic pain states harboring a neuropathic component

Abstract AbstractNeuropathic pain is an integral component of several chronic pain conditions and poses a major health problem worldwide. Despite emerging understanding of mechanisms behind neuropathic pain, the available treatment options are still limited in efficacy or associated with side effects, therefore making it necessary to find viable alternatives. In a genetic screen, we recently identified SerpinA3N, a serine protease inhibitor secreted in response to nerve damage by the dorsal root ganglion neurons and we showed that SerpinA3N acts against induction of neuropathic pain by inhibiting the T-cell- and neutrophil-derived protease, leucocyte elastase (LE). In the current study, via detailed in vivo pharmacology combined with analyses of evoked- and spontaneous pain-related behaviors in mice, we report that on systemic delivery, a single dose of 3 independent LE inhibitors can block established nociceptive hypersensitivity in early and late phases in the spared nerve injury model of traumatic neuropathic pain in mice. We further report the strong efficacy of systemic LE inhibitors in reversing ongoing pain in 2 other clinically relevant mouse models—painful diabetic neuropathy and cancer pain. Detailed immunohistochemical analyses on the peripheral tissue samples revealed that both T-Lymphocytes and neutrophils are the sources of LE on peripheral nerve injury, whereas neutrophils are the primary source of LE in diabetic neuropathic conditions. In summary, our re...
Source: Pain - Category: Anesthesiology Tags: Research Paper Source Type: research

Related Links:

ConclusionHemiplegic spontaneous cervical EDH occurs very rarely. It is often misdiagnosed as ischemic stroke and is likely to be administered with thrombolytic agents, making the patient's symptoms worse. Early diagnosis and rapid management of cervical EDH increase the likelihood of complete recovery of the patient's symptoms. Therefore, if there are unilateral weakness and neck pain without cranial nerve dysfunction and there is no evidence of stroke in the brain imaging, spinal EDH should be considered.
Source: Interdisciplinary Neurosurgery - Category: Neurosurgery Source Type: research
We describe the case of a 37-year-old man with a 20-year history of psoriatic arthritis. The patient presented with abdominal pain, watery diarrhea with mild hematochezia, and a reported 24-pound unintentional weight loss over the past five months. Of note, the patient began treatment with etanercept five months earlier after discontinuation of infliximab for his psoriatic arthritis symptoms. Colonoscopy with terminal ileum intubation revealed active colitis and intestinal biopsy results showed marked ulcerations and non-caseating granulomas, indicative of CD. Etanercept was subsequently discontinued and the patient was st...
Source: Journal of Drugs in Dermatology - Category: Dermatology Tags: J Drugs Dermatol Source Type: research
Authors: Alexis AF, Rendon M, Silverberg JI, Pariser DM, Lockshin B, Griffiths CE, Weisman J, Wollenberg A, Chen Z, Davis JD, Li M, Eckert L, Gadkari A, Shumel B, Rossi AB, Graham NM, Ardeleanu M Abstract Dupilumab, a monoclonal antibody that blocks the shared receptor subunit for interleukin (IL)-4 and IL-13, is currently approved for the treatment of adults with inadequately controlled moderate-to-severe atopic dermatitis (AD). The efficacy and safety of dupilumab for AD among racial subgroups is unknown. This post hoc analysis from three phase 3 trials assessed the efficacy and safety of dupilumab vs placebo by ...
Source: Journal of Drugs in Dermatology - Category: Dermatology Tags: J Drugs Dermatol Source Type: research
Authors: Green LJ, Yamauchi PS, Kircik LH Abstract Psoriasis (PsO) is a common, systemic, chronic inflammatory disease characterized by key clinical symptoms, including itching, pain, and scaling, and is associated with substantial physical, psychosocial, and economic health burdens. Currently, there is no cure for PsO; however, the introduction of biologic therapies has revolutionized the clinical management of patients with PsO by expanding treatment options to include multiple therapies with different mechanisms of action targeting cytokines, including tumor necrosis factor inhibitors (TNFis), interleukin (IL)-1...
Source: Journal of Drugs in Dermatology - Category: Dermatology Tags: J Drugs Dermatol Source Type: research
Publication date: Available online 19 August 2019Source: Trends in Food Science &TechnologyAuthor(s): Qingying Fang, Jielun Hu, Qixing Nie, Shaoping NieAbstractBackgroundAs an important role of host homeostasis, the glycometabolism was closely related to the process and metabolic pathways of carbohydrates such as glycolysis, hexosamine biosynthetic pathway, and pentose phosphate in the host. Disorders of glycometabolism result in a series of metabolic diseases, such as diabetes, obesity, hypoglycemia, and etc.Scope and approachPolysaccharides, which were widely existing in daily diet and cannot be directly digested by ...
Source: Trends in Food Science and Technology - Category: Food Science Source Type: research
We examined 9293 individuals from the Copenhagen General Population Study using nuclear magnetic resonance spectroscopy measurements of total cholesterol, free- and esterified cholesterol, triglycerides, phospholipids, and particle concentration. Fourteen subclasses of decreasing size and their lipid constituents were analysed: six subclasses were very low-density lipoprotein (VLDL), one intermediate-density lipoprotein (IDL), three low-density lipoprotein (LDL), and four subclasses were high-density lipoprotein (HDL). Remnant lipoproteins were VLDL and IDL combined. Mean nonfasting cholesterol concentration was 72...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
In conclusion, with study of the frailty syndrome still in its infancy, frailty analysis remains a major challenge. It is a challenge that needs to be overcome in order to shed light on the multiple mechanisms involved in the pathogenesis of this syndrome. Although several mechanisms contribute to frailty, immune system alteration seems to play a central role: this syndrome is characterized by increased levels of pro-inflammatory markers and the resulting pro-inflammatory status can have negative effects on various organs. Future studies should aim to better clarify the immune system alteration in frailty, and seek to esta...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
In this study, we found that senescent chondrocytes isolated from OA patients secrete more EVs compared with nonsenescent chondrocytes. These EVs inhibit cartilage ECM deposition by healthy chondrocytes and can induce a senescent state in nearby cells. We profiled the miR and protein content of EVs isolated from the synovial fluid of OA joints from mice with SnCs. After treatment with a molecule to remove SnCs, termed a senolytic, the composition of EV-associated miR and protein was markedly altered. The senolytic reduced OA development and enhanced chondrogenesis, and these were attributable to several specific differenti...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
In conclusion, the reduction in the analgesic action of opioids in DNP might be a consequence of MOR reduction, particularly in the spinal cord. Therefore, developing opioids of high efficacy might provide analgesia exceeding that of currently available opioids. Introduction Neuropathic pain (NP) is a chronic pain condition that limits patients to fully achieve their daily tasks. Consequently, NP has significant impact on the economic welfare of the society (Bouhassira et al., 2008; Gaskin and Richard, 2012). Therefore, to find drugs satisfactorily treating NP is a major clinical goal. The management of severe acut...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
This study not only provides biological evidence to support the use of duloxetine as the first standard CIPN drug but will also lead to potential new targets for CIPN drug development. Introduction A major dose-limiting complication of chemotherapy is chemotherapy-induced peripheral neuropathy (CIPN). The greatest contributors to CIPN are taxanes (e.g., paclitaxel) and platinum-based (e.g., oxaliplatin) treatments (Krukowski et al., 2015). Paclitaxel (PTX) can effectively treat several of the most common cancers including breast cancer, lung cancer, and ovarian cancer (Ewertz et al., 2015; Cetinkaya-Fisgin et al., ...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
More News: Anesthesiology | Brain | Cancer | Cancer & Oncology | Chronic Pain | Diabetes | Drugs & Pharmacology | Endocrinology | Ganglions | Genetics | Neurology | Pain | Study