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Acne affects most of the world's population, causing an impact on the self-esteem of adolescents and young adults. One of the causes is the presence of the bacteria Cutibacterium acnes which are part of the natural microbiota of the skin. Topical treatments consist of anti-inflammatory and antibiotics, which could select resistant strains. Alternatives to the antibiotic are biocomposites that have antimicrobial activity like biosurfactants which are produced by bacteria. An innovative way of applying these compounds is bioadhesive polymeric films that adhere to the skin and release the active principle topically. Rhamnolipids have great potential to be used in the treatment of acne because they present antimicrobial activity against C. acnes in low and safe concentrations (MIC of 15.62 µg/mL, CBM of 31.25 µg/mL and CC50 of 181.93 µg/mL). Four films with different rhamnolipids concentrations (0.0; 0.1; 0.2; and 0.3%, w/w) were obtained as to visual appearance, mass variation, thickness, density, solubility, pH, water vapor transmission, mechanical properties (folding endurance, bioadhesion strength, tensile strength, elongation at break and Young's modulus), scanning electron microscopy and infrared. The results show that these formulations had a homogeneous appearance; elastic mechanical properties; pH similar to human skin and bioadhesive. The polymeric films containing rhamnolipids were effective against C. acnes, in the in vitro test, at the three concentrations tested, the film with the highest concentration (0.3%, w/w) being the most promising for presenting the highest antimicrobial activity. Thus, the polymeric film containing rhamnolipids has the potential to be used in the treatment of acne.
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Glicolipídeos , Testes de Sensibilidade Microbiana , Polímeros , Glicolipídeos/química , Glicolipídeos/administração & dosagem , Glicolipídeos/farmacologia , Polímeros/química , Testes de Sensibilidade Microbiana/métodos , Antibacterianos/farmacologia , Antibacterianos/administração & dosagem , Antibacterianos/química , Administração Tópica , Propionibacterium acnes/efeitos dos fármacos , Acne Vulgar/tratamento farmacológico , Humanos , Pele/efeitos dos fármacos , Solubilidade , Anti-Infecciosos/farmacologia , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/química , Resistência à Tração , Química Farmacêutica/métodosRESUMO
Neuropathic pain arises from injuries to the nervous system in diseases such as diabetes, infections, toxicity, and traumas. The underlying mechanism of neuropathic pain involves peripheral and central pathological modifications. Peripheral mechanisms entail nerve damage, leading to neuronal hypersensitivity and ectopic action potentials. Central sensitization involves a neuropathological process with increased responsiveness of the nociceptive neurons in the central nervous system (CNS) to their normal or subthreshold input due to persistent stimuli, leading to sustained electrical discharge, synaptic plasticity, and aberrant processing in the CNS. Current treatments, both pharmacological and non-pharmacological, aim to alleviate symptoms but often face challenges due to the complexity of neuropathic pain. Neuromodulation is emerging as an important therapeutic approach for the treatment of neuropathic pain in patients unresponsive to common therapies, by promoting the normalization of neuronal and/or glial activity and by targeting cerebral cortical regions, spinal cord, dorsal root ganglia, and nerve endings. Having a better understanding of the efficacy, adverse events and applicability of neuromodulation through pre-clinical studies is of great importance. Unveiling the mechanisms and characteristics of neuromodulation to manage neuropathic pain is essential to understand how to use it. In the present article, we review the current understanding supporting dorsal root ganglia and spinal cord neuromodulation as a therapeutic approach for neuropathic pain.
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Trans-chalcone (TC) is a flavonoid precursor characterized by a wide spectrum of action, with anti-inflammatory and antioxidant effects. However, no validated methods are available in official compendia for the analysis of this substance. Thus, the aim of this work was to develop and validate a simple, fast, and reproducible spectrophotometric method for the analysis of TC in raw material, and in topical pharmaceutical formulation containing TC. The established conditions were: methanol as extracting solvent, and detection wavelength of 309 nm by UV spectrophotometer. All tests followed the rules of Resolution RDC 166, 2017. The proposed method was selective. Linearity was demonstrated in the concentration range of 1 to 8 µg/mL (r = 0.999). Repeatability and intermediate precision were confirmed by low relative standard deviation values of 1.53% and 2.70% for TC, and of 1.73% and 2.91% for formulation containing TC. Accuracy, evaluated through recovery test, was adequate, with minimum of 98.24% and maximum of 100.23% of recovery. It was observed that the small deliberate modifications done did not interfere with the results, demonstrating the method is robust. The results showed that the method was considered suitable for the intended purpose, inexpensive, easy to apply, selective, linear, precise, accurate, and robust for the determination TC, and pharmaceutical formulation containing TC. Thus, the method developed satisfies the need for an analytical method for the determination of TC, and topical formulation containing TC, being effective, innovative and able to aid in the development of the pharmaceutical field.
Trans-chalcona (TC) é um precursor de flavonoides caracterizado por um amplo espectro de ação, como efeitos anti-inflamatórios e antioxidantes. No entanto, não há método validado disponível em compêndio oficial para análise deste composto. Então, o objetivo deste trabalho foi desenvolver e validar um método espectrofotométrico, simples, rápido e reprodutível para análise de TC em matéria-prima, e em formulação farmacêutica tópica contendo TC. As condições estabelecidas foram: metanol como o solvente de extração, e detecção no comprimento de onda de 309 nm por espectrofotometria no UV. Todos os testes seguiram as normas da RDC 166, 2017. O método proposto foi seletivo. A linearidade foi demonstrada na faixa de concentração de 1 a 8 µg/mL (r = 0.999). A repetibilidade e a precisão intermediária foram confirmadas pelos valores baixos de desvio padrão relativo de 1,53% e 2,70% para a TC, e de 1,73% e 2,91% para a formulação contendo TC. A exatidão, avaliada por meio de testes de recuperação, foi adequada, com mínimo de 98,24% e máximo de 100,04% de recuperação. Observou-se que pequenas modificações no método não interferiram nos resultados, demonstrando que o método é robusto. Os resultados demonstraram que o método foi adequado para a finalidade pretendida, barato, de fácil aplicação, seletivo, linear, preciso, exato e robusto para determinação de TC, e de formulação contendo TC. Então o método desenvolvido satisfaz as necessidades de um método analítico para determinação de TC, e de formulação tópica contendo TC, e é eficaz, inovador e pode contribuir para o desenvolvimento da área farmacêutica.
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AIM: The present study evaluated whether topiramate (TPM) treatment during the peripubertal period affects vascular parameters of male rats and whether oxidative stress plays a role in these changes. MAIN METHODS: Rats were treated with TPM (41 mg/kg/day, gavage) or vehicle (CTR group) from the postnatal day (PND) 28 to 50. At PND 51 and 120 the rats were evaluated for: thoracic aorta reactivity to phenylephrine, in the presence (Endo+) or absence of endothelium (Endo-), to acetylcholine and to sodium nitroprusside (SNP), aortic thickness and endothelial nitric oxide synthase (eNOS) expression. In serum were analyzed: the antioxidant capacity by ferric reducing antioxidant power assay; endogenous antioxidant reduced glutathione, and superoxide anion. Results were expressed as mean ± s.e.m., differences when p < 0.05. STATISTICS: Two-way ANOVA (and Tukey's) or Student t-test. KEY FINDINGS: At PND 51, the contraction induced by phenylephrine in Endo+ ring was higher in TPM when compared to CTR. At PND 120, the aortic sensitivity to acetylcholine in TPM rats was reduced in comparison with CTR. The aortic eNOs expression and the aortic thickness were similar between the groups. At PND 51 and 120, TPM group presented a decrease in antioxidants when compared to CTR groups and at PND 120, in TPM group the superoxide anion was increased. SIGNIFICANCE: Taken together, the treatment of rats with TPM during peripubertal period promoted permanent impairment of endothelial function probably mediated by oxidative stress.
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Acetilcolina , Antioxidantes , Ratos , Animais , Masculino , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Topiramato/farmacologia , Acetilcolina/metabolismo , Superóxidos/metabolismo , Endotélio Vascular/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo , Aorta Torácica/metabolismo , Fenilefrina/farmacologia , Óxido Nítrico/metabolismoRESUMO
INTRODUCTION: Gout arthritis (GA) is an intermittent inflammatory disease affecting approximately 10% of the worldwide population. Symptomatic phases (acute flares) are timely spaced by asymptomatic periods. During an acute attack, redness, joint swelling, limited movement, and excruciating pain are common symptoms. However, the current available therapies are not fully effective in reducing symptoms and offer numerous side effects. Therefore, unveiling new drug targets and effector molecules are required in developing novel GA therapeutics. AREAS COVERED: This review discusses the pathophysiological mechanisms of GA and explores potential pharmacological targets to ameliorate disease outcome. In addition, we listed promising pre-clinical studies demonstrating effector molecules with therapeutical potential. Among those, we emphasized the importance of natural products, including traditional Chinese medicine formulas and their multitarget mechanisms of action. EXPERT OPINION: In our search, we observed that there is a massive gap between pre-clinical and clinical knowledge. Only a minority (4.4%) of clinical trials aimed to intervene by applying natural products or current hot targets described herein. In this sense, we envisage four possibilities for GA therapeutics, which include the repurposing of existing therapies, ALX/FPR2 agonism for improvement in disease outcome, the use of multitarget drugs (e.g. natural products), and targeting the neuroinflammatory component of GA.
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Produtos Biológicos , Gota , Humanos , Gota/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêuticoRESUMO
During an infection, inflammation mobilizes immune cells to eliminate the pathogen and protect the host. However, inflammation can be detrimental when exacerbated and/or chronic. The resolution phase of the inflammatory process is actively orchestrated by the specialized pro-resolving lipid mediators (SPMs), generated from omega-3 and -6 polyunsaturated fatty acids (PUFAs) that bind to different G-protein coupled receptors to exert their activity. As immunoresolvents, SPMs regulate the influx of leukocytes to the inflammatory site, reduce cytokine and chemokine levels, promote bacterial clearance, inhibit the export of viral transcripts, enhance efferocytosis, stimulate tissue healing, and lower antibiotic requirements. Metabolomic studies have evaluated SPM levels in patients and animals during infection, and temporal regulation of SPMs seems to be essential to properly coordinate a response against the microorganism. In this review, we summarize the current knowledge on SPM biosynthesis and classifications, endogenous production profiles and their effects in animal models of bacterial, viral and parasitic infections.
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Ácidos Graxos Ômega-3 , Doenças Parasitárias , Animais , Inflamação/metabolismo , Eicosanoides , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/metabolismo , Citocinas , Mediadores da Inflamação/metabolismoRESUMO
Improved therapies for inflammatory bowel diseases are sorely needed. Novel therapeutic agents and the development of controlled release systems for targeted tissue delivery are interesting approaches to overcome these barriers. We investigated the activity of trans-chalcone (T) in acetic acid-induced colitis in mice and developed, characterized, and determined the therapeutic effect of pectin/casein polymer microcapsules containing T (MT) in a colitis mouse model. In vitro, compound release was achieved in simulated intestinal fluid but not in the simulated gastric fluid. In vivo, since T at the dose of 3 mg/kg but not 0.3 mg/kg ameliorated colitis, we next tested the effects of MT at 0.3 mg/kg (non-effective dose). MT, but not free T at 0.3 mg/kg, significantly improved colitis outcomes such as neutrophil recruitment, antioxidant capacity, cytokine production, and NF-kB activation. This translated into reduced macro and microscopic damage in the colon. T release from the microcapsules is mediated by a pH-dependent and pectinase-regulated mechanism that provide controlled and prolonged release of T. Moreover, MT lowered the required dose for T therapeutic effect, indicating that could be a suitable pharmaceutical approach to colitis treatment. This is the first demonstration that T or MT is effective at reducing the signs of colitis.
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Chalcona , Chalconas , Colite , Camundongos , Animais , Caseínas , Chalcona/farmacologia , Cápsulas/farmacologia , Pectinas , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colo , NF-kappa B , Modelos Animais de DoençasRESUMO
Background: Lipoxin A4 (LXA4) has anti-inflammatory and pro-resolutive roles in inflammation. We evaluated the effects and mechanisms of action of LXA4 in titanium dioxide (TiO2) arthritis, a model of prosthesis-induced joint inflammation and pain. Methods: Mice were stimulated with TiO2 (3mg) in the knee joint followed by LXA4 (0.1, 1, or 10ng/animal) or vehicle (ethanol 3.2% in saline) administration. Pain-like behavior, inflammation, and dosages were performed to assess the effects of LXA4 in vivo. Results: LXA4 reduced mechanical and thermal hyperalgesia, histopathological damage, edema, and recruitment of leukocytes without liver, kidney, or stomach toxicity. LXA4 reduced leukocyte migration and modulated cytokine production. These effects were explained by reduced nuclear factor kappa B (NFκB) activation in recruited macrophages. LXA4 improved antioxidant parameters [reduced glutathione (GSH) and 2,2-azino-bis 3-ethylbenzothiazoline-6-sulfonate (ABTS) levels, nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA and Nrf2 protein expression], reducing reactive oxygen species (ROS) fluorescent detection induced by TiO2 in synovial fluid leukocytes. We observed an increase of lipoxin receptor (ALX/FPR2) in transient receptor potential cation channel subfamily V member 1 (TRPV1)+ DRG nociceptive neurons upon TiO2 inflammation. LXA4 reduced TiO2-induced TRPV1 mRNA expression and protein detection, as well TRPV1 co-staining with p-NFκB, indicating reduction of neuronal activation. LXA4 down-modulated neuronal activation and response to capsaicin (a TRPV1 agonist) and AITC [a transient receptor potential ankyrin 1 (TRPA1) agonist] of DRG neurons. Conclusion: LXA4 might target recruited leukocytes and primary afferent nociceptive neurons to exert analgesic and anti-inflammatory activities in a model resembling what is observed in patients with prosthesis inflammation.
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Artrite , Lipoxinas , Animais , Camundongos , NF-kappa B , Fator 2 Relacionado a NF-E2/genética , Lipoxinas/farmacologia , Líquido Sinovial , Inflamação , Canais de Cátion TRPV/genéticaRESUMO
Intense exposure to UVB radiation incites excessive production of reactive oxygen species (ROS) and inflammation. The resolution of inflammation is an active process orchestrated by a family of lipid molecules that includes AT-RvD1, a specialized proresolving lipid mediator (SPM). AT-RvD1 is derived from omega-3, which presents anti-inflammatory activity and reduces oxidative stress markers. The present work aims to investigate the protective effect of AT-RvD1 on UVB-induced inflammation and oxidative stress in hairless mice. Animals were first treated with 30, 100, and 300 pg/animal AT-RvD1 (i.v.) and then exposed to UVB (4.14 J/cm2). The results showed that 300 pg/animal of AT-RvD1 could restrict skin edema, neutrophil and mast cell infiltration, COX-2 mRNA expression, cytokine release, and MMP-9 activity and restore skin antioxidant capacity as per FRAP and ABTS assays and control O2â¢- production, lipoperoxidation, epidermal thickening, and sunburn cells development. AT-RvD1 could reverse the UVB-induced downregulation of Nrf2 and its downstream targets GSH, catalase, and NOQ-1. Our results suggest that by upregulating the Nrf2 pathway, AT-RvD1 promotes the expression of ARE genes, restoring the skin's natural antioxidant defense against UVB exposition to avoid oxidative stress, inflammation, and tissue damage.
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Antioxidantes , Aspirina , Animais , Camundongos , Antioxidantes/farmacologia , Aspirina/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Inflamação , Ácidos Docosa-Hexaenoicos/farmacologia , Raios UltravioletaRESUMO
Kaurenoic acid (KA) is a diterpene extracted from Sphagneticola trilobata (L.) Pruski. KA presents analgesic properties. However, the analgesic activity and mechanisms of action of KA in neuropathic pain have not been investigated so far; thus, we addressed these points in the present study. A mouse model of neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Acute (at the 7th-day post-CCI surgery) and prolonged (from 7-14th days post-CCI surgery) KA post-treatment inhibited CCI-induced mechanical hyperalgesia at all evaluated time points, as per the electronic version of von Frey filaments. The underlying mechanism of KA was dependent on activating the NO/cGMP/PKG/ATP-sensitive potassium channel signaling pathway since L-NAME, ODQ, KT5823, and glibenclamide abolished KA analgesia. KA reduced the activation of primary afferent sensory neurons, as observed by a reduction in CCI-triggered colocalization of pNF-κB and NeuN in DRG neurons. KA treatment also increased the expression of neuronal nitric oxide synthase (nNOS) at the protein level as well as the intracellular levels of NO in DRG neurons. Therefore, our results provide evidence that KA inhibits CCI neuropathic pain by activating a neuronal analgesic mechanism that depends on nNOS production of NO to silence the nociceptive signaling that generates analgesia.
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Chikungunya virus is an arthropod-borne infectious agent that causes Chikungunya fever disease. About 90% of the infected patients experience intense polyarthralgia, affecting mainly the extremities but also the large joints such as the knees. Chronic disease symptoms persist for months, even after clearance of the virus from the blood. Envelope proteins stimulate the immune response against the Chikungunya virus, becoming an important therapeutic target. We inactivated the Chikungunya virus (iCHIKV) and produced recombinant E2 (rE2) protein and three different types of anti-rE2 monoclonal antibodies. Using these tools, we observed that iCHIKV and rE2 protein induced mechanical hyperalgesia (electronic aesthesiometer test) and thermal hyperalgesia (Hargreaves test) in mice. These behavioral results were accompanied by the activation of dorsal root ganglia (DRG) neurons in mice, as observed by calcium influx. Treatment with three different types of anti-rE2 monoclonal antibodies and absence or blockade (AMG-9810 treatment) of transient receptor potential vanilloid 1 (TRPV1) channel diminished mechanical and thermal hyperalgesia in mice. iCHIKV and rE2 activated TRPV1+ mouse DRG neurons in vitro, demonstrating their ability to activate nociceptor sensory neurons directly. Therefore, our mouse data demonstrate that targeting E2 CHIKV protein with monoclonal antibodies and inhibiting TRPV1 channels are reasonable strategies to control CHIKV pain.
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Anticorpos Monoclonais , Febre de Chikungunya , Vírus Chikungunya , Hiperalgesia , Proteínas do Envelope Viral , Animais , Camundongos , Anticorpos Monoclonais/farmacologia , Anticorpos Antivirais , Antineoplásicos , Hiperalgesia/tratamento farmacológico , Canais de Cátion TRPV , Proteínas do Envelope Viral/metabolismo , Febre de Chikungunya/tratamento farmacológicoRESUMO
Arthroplasty is an orthopedic surgical procedure that replaces a dysfunctional joint by an orthopedic prosthesis, thereby restoring joint function. Upon the use of the joint prosthesis, a wearing process begins, which releases components such as titanium dioxide (TiO2) that trigger an immune response in the periprosthetic tissue, leading to arthritis, arthroplasty failure, and the need for revision. Flavonoids belong to a class of natural polyphenolic compounds that possess antioxidant and anti-inflammatory activities. Hesperidin methyl chalcone's (HMC) analgesic, anti-inflammatory, and antioxidant effects have been investigated in some models, but its activity against the arthritis caused by prosthesis-wearing molecules, such as TiO2, has not been investigated. Mice were treated with HMC (100 mg/kg, intraperitoneally (i.p.)) 24 h after intra-articular injection of 3 mg/joint of TiO2, which was used to induce chronic arthritis. HMC inhibited mechanical hyperalgesia, thermal hyperalgesia, joint edema, leukocyte recruitment, and oxidative stress in the knee joint (alterations in gp91phox, GSH, superoxide anion, and lipid peroxidation) and in recruited leukocytes (total reactive oxygen species and GSH); reduced patellar proteoglycan degradation; and decreased pro-inflammatory cytokine production. HMC also reduced the activation of nociceptor-sensory TRPV1+ and TRPA1+ neurons. These effects occurred without renal, hepatic, or gastric damage. Thus, HMC reduces arthritis triggered by TiO2, a component released upon wearing of prosthesis.
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Artrite , Chalconas , Hesperidina , Camundongos , Animais , Nociceptores/metabolismo , Chalconas/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Artrite/tratamento farmacológico , Estresse Oxidativo , Antioxidantes/farmacologia , Anti-Inflamatórios/farmacologia , Hiperalgesia/tratamento farmacológico , Citocinas/metabolismoRESUMO
Pain can be defined as an unpleasant sensory and emotional experience caused by either actual or potential tissue damage or even resemble that unpleasant experience. For years, science has sought to find treatment alternatives, with minimal side effects, to relieve pain. However, the currently available pharmacological options on the market show significant adverse events. Therefore, the search for a safer and highly efficient analgesic treatment has become a priority. Stem cells (SCs) are non-specialized cells with a high capacity for replication, self-renewal, and a wide range of differentiation possibilities. In this review, we provide evidence that the immune and neuromodulatory properties of SCs can be a valuable tool in the search for ideal treatment strategies for different types of pain. With the advantage of multiple administration routes and dosages, therapies based on SCs for pain relief have demonstrated meaningful results with few downsides. Nonetheless, there are still more questions than answers when it comes to the mechanisms and pathways of pain targeted by SCs. Thus, this is an evolving field that merits further investigation towards the development of SC-based analgesic therapies, and this review will approach all of these aspects.
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UVB-irradiation increases the risk of various skin disorders, therefore leading to inflammation and oxidative stress. In this sense, antioxidant-rich herbs such as Rosmarinus officinalis may be useful in minimizing the damage promoted by reactive oxygen species. In this work, we report the efficacy of a R. officinalis hydroethanolic extract (ROe)-loaded emulgel in preventing UVB-related skin damage. Total phenols were determined using Folin-Ciocalteu assay, and the main phytocomponents in the extract were identified by UHPLC-HRMS. Moreover, in vitro sun protection factor (SPF) value of ROe was also assessed, and we investigated the in vivo protective effect of an emulgel containing ROe against UVB-induced damage in an animal model. The ROe exhibited commercially viable SPF activity (7.56 ± 0.16) and remarkable polyphenolic content (24.15 ± 0.11 mg (Eq.GA)/g). HPLC-MS and UHPLC-HRMS results showcased that the main compounds in ROe were: rosmarinic acid, carnosic acid and carnosol. The evaluation of the in vitro antioxidant activity demonstrated a dose-dependent effect of ROe against several radicals and the capacity to reduce iron. Therefore, we demonstrated that topical application of the formulation containing ROe inhibited edema formation, myeloperoxidase activity, GSH depletion and maintained ferric reducing (FRAP) and ABTS scavenging abilities of the skin after UVB exposure.
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We standardized a model by injecting Ehrlich tumor cells into the paw to evaluate cancer pain mechanisms and pharmacological treatments. Opioid treatment, but not cyclooxygenase inhibitor or tricyclic antidepressant treatments reduces Ehrlich tumor pain. To best use this model for drug screening it is essential to understand its pathophysiological mechanisms. Herein, we investigated the contribution of the transient receptor potential cation channel subfamily V member 1 (TRPV1) in the Ehrlich tumor-induced pain model. Dorsal root ganglia (DRG) neurons from the Ehrlich tumor mice presented higher activity (calcium levels using fluo-4 fluorescent probe) and an increased response to capsaicin (TRPV1 agonist) than the saline-injected animals (p < 0.05). We also observed diminished mechanical (electronic von Frey) and thermal (hot plate) hyperalgesia, paw flinching, and normalization of weight distribution imbalance in TRPV1 deficient mice (p < 0.05). On the other hand, TRPV1 deficiency did not alter paw volume or weight, indicating no significant alteration in tumor growth. Intrathecal injection of AMG9810 (TRPV1 antagonist) reduced ongoing Ehrlich tumor-triggered mechanical and thermal hyperalgesia (p < 0.05). Therefore, the contribution of TRPV1 to Ehrlich tumor pain behavior was revealed by genetic and pharmacological approaches, thus, supporting the use of this model to investigate TRPV1-targeting therapies for the treatment of cancer pain.
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Hesperidin is derived from citrus fruits among other plants. Hesperidin was methylated to increase its solubility, generating hesperidin methyl chalcone (HMC), an emerging flavonoid that possess anti-inflammatory and antioxidant properties. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a powerful regulator of cellular resistance to oxidant products. Previous data evidenced HMC can activate Nrf2 signaling, providing antioxidant protection against diverse pathological conditions. However, its effects on kidney damage caused by non-steroidal anti-inflammatory drugs (NSAIDs) have not been evaluated so far. Mice received a nephrotoxic dose of diclofenac (200 mg/kg) orally followed by intra-peritoneal (i.p.) administration of HMC (0.03-3 mg/kg) or vehicle. Plasmatic levels of urea, creatinine, oxidative stress, and cytokines were assessed. Regarding the kidneys, oxidative parameters, cytokine production, kidney swelling, urine NGAL, histopathology, and Nrf2 mRNA expression and downstream targets were evaluated. HMC dose-dependently targeted diclofenac systemic alterations by decreasing urea and creatinine levels, and lipid peroxidation, as well as IL-6, IFN-γ, and IL-33 production, and restored antioxidant properties in plasma samples. In kidney samples, HMC re-established antioxidant defenses, inhibited lipid peroxidation and pro-inflammatory cytokines and upregulated IL-10, reduced kidney swelling, urine NGAL, and histopathological alterations. Additionally, HMC induced mRNA expression of Nrf2 and its downstream effectors HO-1 and Nqo1, as well as reduced the levels of Keap1 protein detected in renal tissue. The present data demonstrate HMC is a potential compound for the treatment of acute renal damage caused by diclofenac, a routinely prescribed non-steroidal anti-inflammatory drug.
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Maresin-2 (MaR2) is a specialized pro-resolution lipid mediator (SPM) that reduces neutrophil recruitment in zymosan peritonitis. Here, we investigated the analgesic effect of MaR2 and its mechanisms in different mouse models of pain. For that, we used the lipopolysaccharide (LPS)-induced mechanical hyperalgesia (electronic version of the von Frey filaments), thermal hyperalgesia (hot plate test) and weight distribution (static weight bearing), as well as the spontaneous pain models induced by capsaicin (TRPV1 agonist) or AITC (TRPA1 agonist). Immune cell recruitment was determined by immunofluorescence and flow cytometry while changes in the pro-inflammatory mediator landscape were determined using a proteome profiler kit and ELISA after LPS injection. MaR2 treatment was also performed in cultured DRG neurons stimulated with capsaicin or AITC in the presence or absence of LPS. The effect of MaR2 on TRVP1- and TRPA1-dependent CGRP release by cultured DRG neurons was determined by EIA. MaR2 inhibited LPS-induced inflammatory pain and changes in the cytokine landscape as per cytokine array assay. MaR2 also inhibited TRPV1 and TRPA1 activation as observed by a reduction in calcium influx in cultured DRG neurons, and the number of flinches and time spent licking the paw induced by capsaicin or AITC. In corroboration, MaR2 reduced capsaicin- and AITC-induced CGRP release by cultured DRG neurons and immune cell recruitment to the paw skin close the CGRP+ fibers. In conclusion, we show that MaR2 is an analgesic SPM that acts by targeting leukocyte recruitment, nociceptor TRPV1 and TRPA1 activation, and CGRP release in mice.
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Capsaicina , Canais de Potencial de Receptor Transitório , Analgésicos/farmacologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Capsaicina/farmacologia , Citocinas/farmacologia , Ácidos Docosa-Hexaenoicos , Hiperalgesia , Lipopolissacarídeos/farmacologia , Camundongos , Monócitos/metabolismo , Neurônios , Neutrófilos , Nociceptores/metabolismo , Dor , Canal de Cátion TRPA1 , Canais de Cátion TRPVRESUMO
BACKGROUND AND PURPOSE: Gouty arthritis is characterized by an intense inflammatory response to monosodium urate crystals (MSU), which induces severe pain. Current therapies are often ineffective in reducing gout-related pain. Resolvin D1 (RvD1) is a specialized pro-resolving lipid mediator with anti-inflammatory and analgesic proprieties. In this study, we evaluated the effects and mechanisms of action of RvD1 in an experimental mouse model of gouty arthritis, an aim that was not pursued previously in the literature. EXPERIMENTAL APPROACH: Male mice were treated with RvD1 (intrathecally or intraperitoneally) before or after intraarticular stimulation with MSU. Mechanical hyperalgesia was assessed using an electronic von Frey aesthesiometer. Leukocyte recruitment was determined by knee joint wash cell counting and immunofluorescence. IL-1ß production was measured by ELISA. Phosphorylated NF-kB and apoptosis-associated speck-like protein containing CARD (ASC) were detected by immunofluorescence, and mRNA expression was determined by RT-qPCR. CGRP release was determined by EIA and immunofluorescence. MSU crystal phagocytosis was evaluated by confocal microscopy. KEY RESULTS: RvD1 inhibited MSU-induced mechanical hyperalgesia in a dose- and time-dependent manner by reducing leukocyte recruitment and IL-1ß production in the knee joint. Intrathecal RvD1 reduced the activation of peptidergic neurons and macrophages as well as silenced nociceptor to macrophage communication and macrophage function. CGRP stimulated MSU phagocytosis and IL-1ß production by macrophages. RvD1 downmodulated this phenomenon directly by acting on macrophages, and indirectly by inhibiting CGRP release and CGRP-dependent activation of macrophages. CONCLUSIONS AND IMPLICATIONS: This study reveals a hitherto unknown neuro-immune axis in gouty arthritis that is targeted by RvD1.
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Artrite Gotosa , Animais , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/tratamento farmacológico , Peptídeo Relacionado com Gene de Calcitonina , Ácidos Docosa-Hexaenoicos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Inflamação/metabolismo , Ativação de Macrófagos , Masculino , Camundongos , Neuroimunomodulação , Neurônios , Nociceptores/metabolismo , Dor , Ácido Úrico/química , Ácido Úrico/farmacologiaRESUMO
Pimenta pseudocaryophyllus (Gomes) Landrum is a Brazilian native plant. The mechanisms by which it promotes analgesia are unknown. We demonstrated the analgesic effect of P. pseudocaryophyllus dried extract (3 mg/kg; i.p.) in the following models of inflammatory pain (maximal inhibition): phenyl-p-benzoquinone (89%), formalin (72% - 1st phase and 96% - 2nd phase for flinches, and 50% - 1st phase and 71% - 2nd phase for licking behavior), complete Freund's adjuvant (95% - flinches and 33% - licking behavior), and carrageenin (56% - mechanical and 85% - thermal hyperalgesia) without motor impairment. Its analgesic effect depends on inhibiting neutrophil recruitment (95% - histopathology, 83% - myeloperoxidase activity, and 80% - LysM-eGFP mice), oxidative stress (86% - GSH and 98% - superoxide anion), and cytokine production (35% - IL-33, 80% - TNF-α, and 95% - IL-1ß). The present study advances in understanding the analgesic mechanisms of P. pseudocaryophyllus.