cortistatin-14 and Disease-Models--Animal

Cortistatin is a neuropeptide isolated from cortical brain regions, showing high structural homology and sharing many functions with somatostatin. However, cortistatin exerts unique functions in the central nervous and immune systems, including decreasing locomotor activity, inducing sleep-promoting effects, and deactivating inflammatory and T helper (TH )1/TH 17-driven responses in preclinical models of sepsis, arthritis, multiple sclerosis, and colitis. Besides its release by cortical and hippocampal interneurons, cortistatin is produced by macrophages, lymphocytes, and peripheral nociceptive neurons in response to inflammatory stimuli, supporting a physiological role of cortistatin in the immune and nociceptive systems. Cortistatin-deficient mice have been shown to have exacerbated nociceptive responses to neuropathic and inflammatory pain sensitization. However, a paradoxical effect has been observed in studies of immune disorders, in which, despite showing competent inflammatory/autoreactive responses, cortistatin-deficient mice were partially resistant to systemic autoimmunity and inflammation. This unexpected phenotype was associated with elevated circulating glucocorticoids and anxiety-like behavior. These findings support cortistatin as a novel multimodal therapeutic approach to treat autoimmunity and clinical pain and identify it as a key endogenous component of the neuroimmune system related to stress responses.

Topics: Animals; Anti-Inflammatory Agents; Autoimmune Diseases; Cerebral Cortex; Disease Models, Animal; Humans; Inflammation; Macrophages; Mice; Motor Activity; Neuropeptides; Nociceptors; Sleep; Somatostatin; Th1 Cells; Th17 Cells

Mas-related G protein-coupled receptor X2 (MRGPRX2) mediates the itch response in neurons and is involved in atopic dermatitis (AD)-associated inflammation and itch. Potent and MRGPRX2-selective ligands are essential to an understanding of the detailed function of the receptor and to develop new therapeutic agents for its related diseases. (+)-TAN-67 (1), the enantiomer of the δ-opioid receptor (DOR) selective ligand (-)-TAN-67 (1), has been reported to activate MRGPRX2, although (+)-1 also interacts with DOR, which prevents investigators from interrogating the function of MRGPRX2. Here, we have succeeded in developing a novel unnatural morphinan compound (+)-2a by a transformation based on the structure of (+)-1, which removes the DOR binding affinity. (+)-2a activated both human MRGPRX2 and the mouse orthologue Mrgprb2 in in vitro experiments and induced itch-like behaviors in mice to the same extent as (+)-1. The (+)-2a-induced itch response in mice was suppressed by administration of the tripeptide QWF, an MRGPRX2/Mrgprb2 antagonist, or the antipruritic drug nalfurafine. Together, (+)-2a serves as a useful tool to elucidate the itch-related function/action of MRGPRX2 and its mouse orthologue Mrgprb2.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Development; Humans; Ligands; Mice; Molecular Structure; Morphinans; Nerve Tissue Proteins; Pruritus; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Receptors, Opioid, delta; Structure-Activity Relationship

Scleroderma, or systemic sclerosis, is a complex connective tissue disorder characterized by autoimmunity, vasculopathy, and progressive fibrosis of the skin and internal organs. Because its aetiology is unknown, the identification of genes/factors involved in disease severity, differential clinical forms, and associated complications is critical for understanding its pathogenesis and designing novel treatments. Neuroendocrine mediators in the skin emerge as potential candidates. We investigated the role played by the neuropeptide cortistatin in a preclinical model of scleroderma.. Dermal fibrosis was induced by repetitive intradermal injections of bleomycin in wild-type and cortistatin-deficient mice. The histopathological signs and expression of fibrotic markers were evaluated in the skin and lungs.. An inverse correlation between cortistatin levels and fibrogenic activation exists in the damaged skin and dermal fibroblasts. Bleomycin-challenged skin lesions of mice that are partially and totally deficient in cortistatin showed exacerbated histopathological signs of scleroderma, characterized by thicker and more fibrotic dermal layer, enlarged epidermis, and increased inflammatory infiltration in comparison to those of wild-type mice. Cortistatin deficiency enhanced dermal collagen deposits, connective tissue growth factor expression, loss of microvessels, and predisposition to suffer severe complications that co-occur with dermal exposition to bleomycin, including pulmonary fibrotic disease and increased mortality. Treatment with cortistatin mitigated these pathological processes.. We identify cortistatin as an endogenous break of skin inflammation and fibrosis. Deficiency in cortistatin could be a marker of poor prognosis of scleroderma and associated complications. Cortistatin-based therapies emerge as attractive candidates to treat severe forms of systemic sclerosis and to manage fibrosis-related side effects of bleomycin chemotherapy in oncologic patients.

Topics: Animals; Bleomycin; Disease Models, Animal; Fibrosis; Mice; Neuropeptides; Pulmonary Fibrosis; Scleroderma, Systemic

Ulcerative colitis and Crohn's disease are forms of inflammatory bowel disease whose incidence and prevalence are increasing worldwide. These diseases lead to chronic inflammation of the gastrointestinal tract as a result of an abnormal response of the immune system. Recent studies positioned Cortistatin, which shows low stability in plasma, as a candidate for IBD treatment. Here, using NMR structural information, we design five Cortistatin analogues adopting selected native Cortistatin conformations in solution. One of them, A5, preserves the anti-inflammatory and immunomodulatory activities of Cortistatin in vitro and in mouse models of the disease. Additionally, A5 displays an increased half-life in serum and a unique receptor binding profile, thereby overcoming the limitations of the native Cortistatin as a therapeutic agent. This study provides an efficient approach to the rational design of Cortistatin analogues and opens up new possibilities for the treatment of patients that fail to respond to other therapies.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cells, Cultured; Colitis, Ulcerative; Dextran Sulfate; Disease Models, Animal; Gastrointestinal Tract; Humans; Immunologic Factors; Immunomodulation; Inflammation; Male; Mice; Mice, Inbred C57BL; Molecular Conformation; Neuropeptides; Trinitrobenzenesulfonic Acid

Acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and pulmonary fibrosis remain major causes of morbidity, mortality and a healthcare burden in critically ill patient. There is an urgent need to identify factors causing susceptibility and for the design of new therapeutic agents. Here, we evaluate the effectiveness of the immunomodulatory neuropeptide cortistatin to regulate pulmonary inflammation and fibrosis in vivo.. ALI/ARDS and pulmonary fibrosis were induced experimentally in wild-type and cortistatin-deficient mice by pulmonary infusion of the bacterial endotoxin LPS or the chemotherapeutic drug bleomycin, and the histopathological signs, pulmonary leukocyte infiltration and cytokines, and fibrotic markers were evaluated.. Partially deficient mice in cortistatin showed exacerbated pulmonary damage, pulmonary inflammation, alveolar oedema and fibrosis, and subsequent increased respiratory failure and mortality when challenged to LPS or bleomycin, even at low doses. Treatment with cortistatin reversed these aggravated phenotypes and protected from progression to severe ARDS and fibrosis, after high exposure to both injury agents. Moreover, cortistatin-deficient pulmonary macrophages and fibroblasts showed exaggerated ex vivo inflammatory and fibrotic responses, and treatment with cortistatin impaired their activation. Finally, the protective effects of cortistatin in ALI and pulmonary fibrosis were partially inhibited by specific antagonists for somatostatin and ghrelin receptors.. We identified cortistatin as an endogenous inhibitor of pulmonary inflammation and fibrosis. Deficiency in cortistatin could be a marker of poor prognosis in inflammatory/fibrotic pulmonary disorders. Cortistatin-based therapies could emerge as attractive candidates to treat severe ALI/ARDS, including SARS-CoV-2-associated ARDS.

Topics: Animals; Disease Models, Animal; Fibrosis; Inflammation; Lipopolysaccharides; Lung; Mice; Neuropeptides; Pneumonia

Topics: Adult; Aged; Animals; Cells, Cultured; Disease Models, Animal; Female; Humans; Inflammasomes; Intervertebral Disc Degeneration; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Mitochondria; Neuropeptides; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Nucleus Pulposus; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Signal Transduction; Young Adult

Asthma is a chronic inflammatory disease affecting millions of people around the world, yet much remains unknown about its underlying mechanisms. Cortistatin (CST) is a neuropeptide which is reported to be a potential endogenous anti-inflammatory factor in several conditions. To testify the potential involvement of CST in airway inflammatory reaction, an ovalbumin (OVA)-induced mice model was established in wild-type (WT) as well as CST-knockout (Cort

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Chemokine CCL2; Disease Models, Animal; Lung; Male; Mice, Knockout; Neuropeptides; NF-kappa B; Ovalbumin; Signal Transduction

To evaluate the anti-inflammatory effect of cortistatin (CST) in endotoxin-induced uveitis (EIU) model and to compare the results with corticosteroid treatment.. A total of 35 healthy Wistar albino rats were randomly divided into five groups. EIU was induced by a single subcutaneous injection of lipopolysaccharide (LPS). Group I received intraperitoneal (ip) normal saline (NS), Group II received ip 150 μg LPS plus NS, Group III received ip 150 μg LPS plus 250 μg/kg CST, Group IV received ip 150 μg LPS plus 1mg/kg dexamethasone, and Group V received ip 250 μg/kg CST only. The aqueous humor was collected 24 h after injection and the infiltrating cells were determined. Moreover, histopathological and immunohistochemical examinations were also performed.. The clinical score and infiltrated cell count were reduced in Groups III and IV compared with Group II (P < 0.001). The pathological findings of Groups III and IV were significantly reduced compared with Group II (P < 0.001). These findings were similar between Groups III and IV (P = 1.000). Tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL-1β) immunoreactivity in the ciliary body of Group III and Group IV were significantly reduced compared with Group II (P < 0.001). TNF-α and IL-1β immunoreactivity in the ciliary body of Group III and Group IV were similar compared with Group I and Group V (range of P values was 0.539-0.958).. CST administration as a therapeutic agent might ameliorate the severity of intraocular inflammation in uveitis patients. In conclusion, effect of CST and dexamethasone in EIU model was comparable.

Topics: Animals; Anti-Inflammatory Agents; Aqueous Humor; Disease Models, Animal; Endotoxins; Humans; Neuropeptides; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha; Uveitis

Osteoarthritis (OA) is a common degenerative disease, and tumor necrosis factor (TNF-α) is known to play a critical role in OA. Cortistatin (CST) is a neuropeptide discovered over 20  years ago, which plays a vital role in inflammatory reactions. However, it is unknown whether CST is involved in cartilage degeneration and OA development.. The interaction between CST and TNF-α receptors was investigated through Coimmunoprecipitation and Biotin-based solid-phase binding assay. Western blot, Real-time PCR, ELISA, immunofluorescence staining, nitrite production assay and DMMB assay of GAG were performed for the primary chondrocyte experiments. Surgically induced and spontaneous OA models were established and western blot, flow cytometry, Real-time PCR, ELISA, immunohistochemistry and fluorescence in vivo imaging were performed for in vivo experiments.. CST competitively bound to TNFR1 as well as TNFR2. CST suppressed proinflammatory function of TNF-α. Both spontaneous and surgically induced OA models indicated that deficiency of CST led to an accelerated OA-like phenotype, while exogenous CST attenuated OA development in vivo. Additionally, TNFR1- and TNFR2-knockout mice were used for analysis and indicated that TNFRs might be involved in the protective role of CST in OA. CST inhibited activation of the NF-κB signaling pathway in OA.. This study provides new insight into the pathogenesis and therapeutic strategy of cartilage degenerative diseases, including OA. FUND: The National Natural Science Foundation of China, the Natural Science Foundation of Shandong Province, Key Research and Development Projects of Shandong Province and the Cross-disciplinary Fund of Shandong University.

Topics: Animals; Cartilage, Articular; Caspase 3; Chondrocytes; Disease Models, Animal; Humans; Interleukin-1beta; Knee Joint; Matrix Metalloproteinase 13; Mice, Inbred C57BL; Mice, Knockout; Neuropeptides; NF-kappa B; Osteoarthritis; Protein Binding; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Signal Transduction; Tumor Necrosis Factor-alpha

Topics: Angiotensin II; Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Apoptosis; Cell Line; Disease Models, Animal; Elastin; Male; MAP Kinase Signaling System; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Knockout, ApoE; Myocytes, Smooth Muscle; Neuropeptides; Proteolysis; Reactive Oxygen Species

Cortistatin (CST) is a newly discovered endogenous active peptide that exerts protective effects on the cardiovascular system. However, the relationship between CST and aortic calcification and the underlying mechanism remain obscure. Therefore, we investigated effects of CST on aortic calcification and its signalling pathways.. Calcium content and alkaline phosphatase (ALP) activity were measured using the o-cresolphthalein colorimetric method and ALP assay kit respectively. Protein expression of smooth muscle (SM)-ɑ-actin, osteocalcin (OCN), β-catenin, glycogen synthase kinase 3β (GSK3β), p-GSK3β, protein kinase C (PKC), p-PKC, c-Jun N-terminal kinase (JNK) and p-JNK was determined using Western blotting.. In aorta from a rat vitamin D3 calcification model, CST abrogated calcium deposition and pathological damage, decreased the protein expression of OCN and β-catenin and increased SM-ɑ-actin expression. In a rat cultured vascular smooth muscular cell (VSMC) calcification model induced by β-glycerophosphate (β-GP), CST inhibited the increase in ALP activity, calcium content and OCN protein and the decrease in SM-α-actin expression. CST also inhibited the β-GP-induced increase in p-GSK3β and β-catenin protein (both P < .05). The inhibitory effects of CST on ALP activity, calcium deposition and β-catenin protein were abolished by pretreatment with lithium chloride, a GSK3β inhibitor. CST promoted the protein expression of p-PKC by 68.5% (P < .01), but not p-JNK. The ability of CST to attenuate β-GP-induced increase in ALP activity, calcium content and OCN expression in the VSMC model was abolished by pretreatment with the PKC inhibitor Go6976.. These results indicate that CST inhibits aortic calcification and osteogenic differentiation of VSMCs likely via the GSK3β/β-catenin and PKC signalling pathways, but not JNK signalling pathway.

Topics: Animals; beta Catenin; Cholecalciferol; Disease Models, Animal; Glycerophosphates; Glycogen Synthase Kinase 3 beta; Male; MAP Kinase Signaling System; Myocytes, Smooth Muscle; Neuropeptides; Osteogenesis; Primary Cell Culture; Protein Kinase C; Rats, Sprague-Dawley; Vascular Calcification

Many women who take antidepressant medications become pregnant while taking their medication; however, the impact of depression and antidepressant medication on fetal development is not well understood. This study used a translational animal model of maternal depression to investigate the consequences of discontinuing antidepressant medication during pregnancy. First, rats received corticosterone (CORT; 40 mg/kg, s.c.) or vehicle to induce a depressive-like phenotype. After 16 days of treatment with CORT or vehicle, animals were treated with sertraline (a selective serotonin reuptake inhibitor, SSRI; 20 mg/kg) or vehicle via gavage. Following 21 days of CORT or oil treatment, rats were mated. One group receiving sertraline was discontinued from treatment on gestational day 16, and another group continued sertraline treatment throughout pregnancy to assess the effects of discontinuation. After weaning, dams were sacrificed via perfusion to investigate neurogenesis. As intended, CORT administration created a depressive-like phenotype with increased immobility in the Forced Swim Test and reduced body weight. Interestingly, sertraline treatment could not rescue these altered features. Pre-conceptional CORT exposure resulted in smaller litters and CORT dams that received sertraline until the end of gestation spent more time off of the nest compared to CORT dams that received vehicle or discontinued sertraline during gestation. There was no difference in hippocampal neurogenesis between any of the groups. Our results suggest that treatment with antidepressants may have different effects in healthy or depressed dams, however, we need more research to investigate the detailed and long-term effects of maternal depression and its treatment in translational animal models.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Corticosterone; Depression; Depression, Postpartum; Depressive Disorder; Disease Models, Animal; Female; Hippocampus; Maternal Behavior; Neuropeptides; Postpartum Period; Pregnancy; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Stress, Physiological

Atherosclerosis is a chronic inflammatory cardiovascular disease that is responsible of high mortality worldwide. Evidence indicates that maladaptive autoimmune responses in the arterial wall play critical roles in the process of atherosclerosis. Cortistatin is a neuropeptide expressed in the vascular system and atherosclerotic plaques that regulates vascular calcification and neointimal formation, and inhibits inflammation in different experimental models of autoimmune diseases. Its role in inflammatory cardiovascular disorders is largely unexplored. The aim of this study is to investigate the potential therapeutic effects of cortistatin in two well-established preclinical models of atherosclerosis, and the molecular and cellular mechanisms involved. Systemic treatment with cortistatin reduced the number and size of atherosclerotic plaques in carotid artery, heart, aortic arch and aorta in acute and chronic atherosclerosis induced in apolipoprotein E-deficient mice fed a high-lipid diet. This effect was exerted at multiple levels. Cortistatin reduced Th1/Th17-driven inflammatory responses and increased regulatory T cells in atherosclerotic arteries and lymphoid organs. Moreover, cortistatin reduced the capacity of endothelial cells to bind and recruit immune cells to the plaque and impaired the formation of foam cells by enhancing cholesterol efflux from macrophages. Cortistatin emerges as a new candidate for the treatment of the clinical manifestations of atherosclerosis.

Topics: Animals; Anti-Inflammatory Agents; Diet, High-Fat; Disease Models, Animal; Female; Foam Cells; Hyperlipidemias; Mice; Mice, Knockout, ApoE; Neuropeptides; Plaque, Atherosclerotic; T-Lymphocytes, Regulatory; Th1 Cells; Th17 Cells

Myocarditis is an inflammatory and autoimmune cardiovascular disease that causes dilated myocardiopathy and is responsible for high morbidity and mortality worldwide. Cortistatin is a neuropeptide produced by neurons and cells of the immune and vascular systems. Besides its action in locomotor activity and sleep, cortistatin inhibits inflammation in different experimental models of autoimmune diseases. However, its role in inflammatory cardiovascular disorders is unexplored. Here, we investigated the therapeutic effects of cortistatin in a well-established preclinical model of experimental autoimmune myocarditis (EAM).. We induced EAM by immunization with a fragment of cardiac myosin in susceptible Balb/c mice. Cortistatin was administered i.p. starting 7, 11 or 15 days after EAM induction. At day 21, we evaluated heart hypertrophy, myocardial injury, cardiac inflammatory infiltration and levels of serum and cardiac inflammatory cytokines, cortistatin and autoantibodies. We determined proliferation and cytokine production by heart draining lymph node cells in response to cardiac myosin restimulation.. Systemic injection of cortistatin during the effector phase of the disease significantly reduced its prevalence and signs of heart hypertrophy and injury (decreased the levels of brain natriuretic peptide) and impaired myocardial inflammatory cell infiltration. This effect was accompanied by a reduction in self-antigen-specific T-cell responses in lymph nodes and in the levels of cardiomyogenic antibodies and inflammatory cytokines in serum and myocardium. Finally, we found a positive correlation between cardiac and systemic cortistatin levels and EAM severity.. Cortistatin emerges as a new candidate to treat inflammatory dilated cardiomyopathy.

Topics: Animals; Autoimmune Diseases; Cardiomyopathy, Dilated; Cytokines; Disease Models, Animal; Female; Inflammation; Lymph Nodes; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Myocarditis; Neuropeptides; Severity of Illness Index; T-Lymphocytes; Time Factors

Somatostatin (SST) and cortistatin (CORT) regulate numerous endocrine secretions and their absence [knockout (KO)-models] causes important endocrine-metabolic alterations, including pituitary dysregulations. We have demonstrated that the metabolic phenotype of single or combined SST/CORT KO-models is not drastically altered under normal conditions. However, the biological actions of SST/CORT are conditioned by the metabolic-status (e.g. obesity). Therefore, we used male/female SST- and CORT-KO mice fed low-fat (LF) or high-fat (HF) diet to explore the interplay between SST/CORT and obesity in the control of relevant pituitary-axes and whole-body metabolism. Our results showed that the SST/CORT role in the control of GH/prolactin secretions is maintained under LF- and HF-diet conditions as SST-KOs presented higher GH/prolactin-levels, while CORT-KOs displayed higher GH- and lower prolactin-levels than controls under both diets. Moreover, the impact of lack of SST/CORT on the metabolic-function was gender- and diet-dependent. Particularly, SST-KOs were more sensitive to HF-diet, exhibiting altered growth and body-composition (fat/lean percentage) and impaired glucose/insulin-metabolism, especially in males. Conversely, only males CORT-KO under LF-diet conditions exhibited significant alterations, displaying higher glucose-levels and insulin-resistance. Altogether, these data demonstrate a tight interplay between SST/CORT-axis and the metabolic status in the control of endocrine/metabolic functions and unveil a clear dissociation of SST/CORT roles.

Topics: Animals; Dietary Fats; Disease Models, Animal; Female; Homeostasis; Male; Mice; Mice, Knockout; Neuropeptides; Obesity; Pituitary Gland; Sex Characteristics; Somatostatin

Clinical pain, as a consequence of inflammation or injury of peripheral organs (inflammatory pain) or nerve injury (neuropathic pain), represents a serious public health issue. Treatment of pain-related suffering requires knowledge of how pain signals are initially interpreted and subsequently transmitted and perpetuated. To limit duration and intensity of pain, inhibitory signals participate in pain perception. Cortistatin is a cyclic-neuropeptide that exerts potent inhibitory actions on cortical neurons and immune cells. Here, we found that cortistatin is a natural analgesic component of the peripheral nociceptive system produced by peptidergic nociceptive neurons of the dorsal root ganglia in response to inflammatory and noxious stimuli. Moreover, cortistatin is produced by GABAergic interneurons of deep layers of dorsal horn of spinal cord. By using cortistatin-deficient mice, we demonstrated that endogenous cortistatin critically tunes pain perception in physiological and pathological states. Furthermore, peripheral and spinal injection of cortistatin potently reduced nocifensive behavior, heat hyperalgesia and tactile allodynia in experimental models of clinical pain evoked by chronic inflammation, surgery and arthritis. The analgesic effects of cortistatin were independent of its anti-inflammatory activity and directly exerted on peripheral and central nociceptive terminals via Gαi-coupled somatostatin-receptors (mainly sstr2) and blocking intracellular signaling that drives neuronal plasticity including protein kinase A-, calcium- and Akt/ERK-mediated release of nociceptive peptides. Moreover, cortistatin could modulate, through its binding to ghrelin-receptor (GHSR1), pain-induced sensitization of secondary neurons in spinal cord. Therefore, cortistatin emerges as an anti-inflammatory factor with potent analgesic effects that offers a new approach to clinical pain therapy, especially in inflammatory states.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cells, Cultured; Disease Models, Animal; Drug Administration Routes; Female; Ganglia, Spinal; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Neurons; Neuropeptides; Nitrobenzenes; Pain; Pain Measurement; Pain Threshold; Spinal Cord; Sulfonamides; Time Factors

To investigate the role of the antiinflammatory neuropeptide cortistatin in chronic pain evoked by joint inflammation.. Thermal and mechanical hyperalgesia was evoked in mouse knee joints by intraplantar injection of tumor necrosis factor α and intraarticular infusion of Freund's complete adjuvant, and the analgesic effects of cortistatin, administered centrally, peripherally, and systemically, were assessed. In addition, the effects of cortistatin on the production of nociceptive peptides and the activation of pain signaling were assayed in dorsal root ganglion cultures and in inflammatory pain models. The role of endogenous cortistatin in pain sensitization and perpetuation of chronic inflammatory states was evaluated in cortistatin-deficient mice. Finally, the effect of noxious/inflammatory stimuli in the production of cortistatin by the peripheral nociceptive system was assayed in vitro and in vivo.. Expression of cortistatin was observed in peptidergic nociceptors of the peripheral nociceptive system, and endogenous cortistatin was found to participate in the tuning of pain sensitization, especially in pathologic inflammatory conditions. Results showed that cortistatin acted both peripherally and centrally to reduce the tactile allodynia and heat hyperalgesia evoked by arthritis and peripheral tissue inflammation in mice, via mechanisms that were independent of its antiinflammatory action. These mechanisms involved direct action on nociceptive neurons and regulation of central sensitization. The analgesic effects of cortistatin in murine arthritic pain were linked to binding of the neuropeptide to somatostatin and ghrelin receptors, activation of the G protein subunit Gαi , impairment of ERK signaling, and decreased production of calcitonin gene-related peptide in primary nociceptors.. These findings indicate that cortistatin is an antiinflammatory factor with potent analgesic effects that may offer a new approach to pain therapy in pathologic inflammatory states, including osteoarthritis and rheumatoid arthritis.

Topics: Analgesia; Animals; Arthritis; Calcitonin Gene-Related Peptide; Central Nervous System Sensitization; Disease Models, Animal; Drug Therapy, Combination; Female; Freund's Adjuvant; Ghrelin; GTP-Binding Protein alpha Subunits; Hyperalgesia; Injections, Intra-Articular; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuropeptides; Pain; Pain Threshold; Protein Binding; Receptors, Ghrelin; Receptors, Somatostatin; Somatostatin; Stifle; Tumor Necrosis Factor-alpha

There are fewer reports of brain infection by Klebsiella pneumoniae than there are in other organs, but an increase incidence and morbidity has been noted. We have previously developed a rat model of K. pneumoniae meningoencephalitis. Cortistatin (CST) is a recently discovered neuropeptide with endocrine activities in humans. In this study, we found that brain infection by K. pneumoniae increased endogenous prepro-CST messenger RNA expression, which occurred earlier than did leukocyte infiltration in vivo and also occurred in cultured neuron-glia. Postinfection treatment with CST (either intracerebroventricularly or intraperitoneally), but not somatostatin, reduced leukocyte recruitment and clinical illness as revealed by fever and clinical score in vivo. Postinfection increases of proinflammatory cytokine messenger RNA levels were attenuated by CST in neuron-glia cultures, further confirming a direct effect on neuroinflammation. Administration of CST resulted in less postinfection neuronal loss in vitro, suggesting a direct neuroprotective effect and potential as an adjuvant for treating bacterial meningoencephalitis.

Topics: Animals; Anti-Inflammatory Agents; Cerebral Cortex; Cytokines; Disease Models, Animal; Hippocampus; Klebsiella Infections; Klebsiella pneumoniae; Leukocytosis; Male; Meningoencephalitis; Necrosis; Neurogenic Inflammation; Neuroimmunomodulation; Neuropeptides; Neuroprotective Agents; Rats; Rats, Sprague-Dawley

Rheumatoid arthritis is a chronic autoimmune disease of unknown aetiology characterised by chronic inflammation in the joints and subsequent destruction of the cartilage and bone.. To propose a new strategy for the treatment of arthritis based on the administration of cortistatin, a newly discovered neuropeptide with anti-inflammatory actions.. DBA/1J mice with collagen-induced arthritis were treated with cortistatin after the onset of disease, and the clinical score and joint histopathology were evaluated. Inflammatory response was determined by measuring the levels of various inflammatory mediators (cytokines and chemokines) in joints and serum. T helper cell type 1 (Th1)-mediated autoreactive response was evaluated by determining the proliferative response and cytokine profile of draining lymph node cells stimulated with collagen and by assaying the content of serum autoantibodies.. Cortistatin treatment significantly reduced the severity of established collagen-induced arthritis, completely abrogating joint swelling and destruction of cartilage and bone. The therapeutic effect of cortistatin was associated with a striking reduction in the two deleterious components of the disease-that is, the Th1-driven autoimmune and inflammatory responses. Cortistatin downregulated the production of various inflammatory cytokines and chemokines, decreased the antigen-specific Th1-cell expansion, and induced the production of regulatory cytokines, such as interleukin 10 and transforming growth factor beta1. Cortistatin exerted its effects on synovial cells through both somatostatin and ghrelin receptors, showing a higher effect than both peptides protecting against experimental arthritis.. This work provides a powerful rationale for the assessment of the efficacy of cortistatin as a novel therapeutic approach to the treatment of rheumatoid arthritis.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Collagen Type II; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Immunoglobulins; Mice; Mice, Inbred DBA; Neuropeptides; Receptors, G-Protein-Coupled; Receptors, Ghrelin; Receptors, Somatostatin; Severity of Illness Index; Synovial Membrane; Th1 Cells; Treatment Outcome

Cortistatin is a recently discovered cyclic neuropeptide related to somatostatin that has emerged as a potential endogenous antiinflammatory factor based on its production by, and binding to, immune cells. Crohn's disease is a chronic debilitating disease characterized by severe T helper 1 (Th1)-driven inflammation of the gastrointestinal tract. The aim of this study is to investigate the therapeutic effect of cortistatin in a murine model of colitis. Cortistatin treatment significantly ameliorated the clinical and histopathologic severity of the inflammatory colitis, abrogating body weight loss, diarrhea, and inflammation and increased the survival rate of the colitic mice. The therapeutic effect was associated with down-regulation of inflammatory and Th1-driven autoimmune response, including the regulation of a wide spectrum of inflammatory mediators. In addition, a partial involvement of regulatory IL-10-secreting T cells in this therapeutic effect was demonstrated. Importantly, cortistatin treatment was therapeutically effective in established colitis and avoided the recurrence of the disease. This work identifies cortistatin as an antiinflammatory factor with the capacity to deactivate the intestinal inflammatory response and restore mucosal immune tolerance at multiple levels. Consequently, cortistatin represents a multistep therapeutic approach for the treatment of Crohn's disease and other Th1-mediated inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cytokines; Disease Models, Animal; Humans; Immunity, Mucosal; In Vitro Techniques; Inflammation Mediators; Inflammatory Bowel Diseases; Macrophages; Mice; Mice, Inbred BALB C; Neuropeptides; Th1 Cells; Trinitrobenzenesulfonic Acid