RESUMO
Capsaicin-sensitive peptidergic sensory nerves play complex, mainly protective regulatory roles in the inflammatory cascade of the joints via neuropeptide mediators, but the mechanisms of the hyperacute arthritis phase has not been investigated. Therefore, we studied the involvement of these afferents in the early, "black box" period of a rheumatoid arthritis (RA) mouse model. Capsaicin-sensitive fibres were defunctionalized by pretreatment with the ultrapotent capsaicin analog resiniferatoxin and arthritis was induced by K/BxN arthritogenic serum. Disease severity was assessed by clinical scoring, reactive oxygen species (ROS) burst by chemiluminescent, vascular permeability by fluorescent in vivo imaging. Contrast-enhanced magnetic resonance imaging was used to correlate the functional and morphological changes. After sensory desensitization, both early phase ROS-burst and vascular leakage were significantly enhanced, which was later followed by the increased clinical severity scores. Furthermore, the early vascular leakage and ROS-burst were found to be good predictors of later arthritis severity. We conclude that the anti-inflammatory role of peptidergic afferents depends on their activity in the hyperacute phase, characterized by decreased cellular and vascular inflammatory components presumably via anti-inflammatory neuropeptide release. Therefore, these fibres might serve as important gatekeepers in RA.
Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Capsaicina/farmacologia , Inflamação Neurogênica/prevenção & controle , Neuropeptídeos/farmacologia , Fármacos do Sistema Sensorial/farmacologia , Animais , Artrite Experimental/etiologia , Artrite Experimental/patologia , Artrite Reumatoide/etiologia , Artrite Reumatoide/patologia , Diterpenos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Espécies Reativas de Oxigênio/metabolismoRESUMO
Two main contributors of sterile neurogenic inflammation underlying migraine pain, calcitonin gene-related peptide (CGRP), and meningeal mast cells (MMCs) play a key role in the activation of the inflammatory cascade resulting in the sensitization of trigeminal nociceptors. It is well established that phytochemical agent thymoquinone exhibits multiple anti-inflammatory effects in different in vitro and in vivo models of neuroinflammation. But its effects on the CGRP release and meningeal mast cells are unknown. In the present study, we investigated the effects of thymoquinone on the CGRP release in migraine-related strategic structures which are crucial targets for anti-migraine drugs, and on the MMCs in glyceryl trinitrate (GTN)-induced in vivo migraine model as well as in the ex vivo meningeal preparations in rats. Anti-inflammatory thymoquinone ameliorated GTN-stimulated CGRP levels in plasma, and migraine-related structures including trigeminal ganglion and brainstem; moreover, thymoquinone inhibited degranulation of MMCs and prevented the increase in the number of MMCs in GTN-induced in vivo migraine model. However, in the ex vivo meningeal preparations, thymoquinone did not inhibit the GTN-induced CGRP release from trigeminal meningeal afferents. Our findings suggest that thymoquinone mediates modulation of CGRP release in trigeminal ganglion neurons and brainstem, and stabilization of MMCs. Thus, thymoquinone may be a promising candidate to prevent the meningeal neurogenic inflammation and consequently migraine.
Assuntos
Anti-Inflamatórios/farmacologia , Benzoquinonas/farmacologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Mastócitos/metabolismo , Transtornos de Enxaqueca/tratamento farmacológico , Inflamação Neurogênica/prevenção & controle , Animais , Peptídeo Relacionado com Gene de Calcitonina/sangue , Modelos Animais de Doenças , Masculino , Meninges/citologia , Transtornos de Enxaqueca/induzido quimicamente , Inflamação Neurogênica/tratamento farmacológico , Nitroglicerina/toxicidade , Compostos Fitoquímicos/farmacologia , Ratos , Ratos WistarRESUMO
Nicotine improves endotoxic manifestations of hypotension and cardiac autonomic dysfunction in rats. Here, we test the hypothesis that brainstem antiinflammatory pathways of α7/α4ß2 nicotinic acetylcholine receptors (nAChRs) modulate endotoxic cardiovascular derangements. Pharmacologic and molecular studies were performed to determine the influence of nicotine or selective α7/α4ß2-nAChR ligands on cardiovascular derangements and brainstem neuroinflammation caused by endotoxemia in conscious rats. The i.v. administration of nicotine (50⯵g/kg) abolished the lipopolysaccharide (LPS, 10â¯mg/kg i.v.)-evoked: (i) falls in blood pressure and spectral measure of cardiac sympathovagal balance (ratio of the low-frequency to high-frequency power, LF/HF), (ii) elevations in immunohistochemical protein expressions of NFκB and α4ß2-nAChR in medullary neurons of the nucleus tractus solitarius (NTS) and rostral ventrolateral medulla (RVLM), and (iii) decreases in medullary α7-nAChR protein expression. These favorable nicotine influences were replicated in rats treated intracisternally (i.c.) with PHA-543613 (selective α7-nAChR agonist) or 5-iodo-A-85380 (5IA, selective α4ß2-nAChRs agonist). Measurement of arterial baroreflex activity by the vasoactive method revealed that nicotine, PHA, or 5IA reversed the LPS depression of reflex bradycardic, but not tachycardic, activity. Moreover, the counteraction by nicotine of LPS hypotension was mostly inhibited after treatment with i.c. methyllycaconitine (MLA, α7-nAChR antagonist) in contrast to a smaller effect for dihydro-ß-erythroidine (DHßE, α4ß2-nAChR antagonist), whereas the associated increases in LF/HF ratio remained unaltered. The data signifies the importance of brainstem α7, and to a lesser extent α4ß2, receptors in the nicotine counteraction of detrimental cardiovascular and neuroinflammatory consequences of endotoxemia.
Assuntos
Fibras Colinérgicas/fisiologia , Endotoxemia/prevenção & controle , Hipotensão/prevenção & controle , NF-kappa B/biossíntese , Inflamação Neurogênica/prevenção & controle , Receptores Nicotínicos/biossíntese , Receptor Nicotínico de Acetilcolina alfa7/biossíntese , Aconitina/análogos & derivados , Aconitina/farmacologia , Animais , Azetidinas/farmacologia , Bradicardia/complicações , Bradicardia/prevenção & controle , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Di-Hidro-beta-Eritroidina/farmacologia , Endotoxemia/complicações , Hipotensão/induzido quimicamente , Hipotensão/complicações , Infusões Intraventriculares , Lipopolissacarídeos , Masculino , Bulbo/metabolismo , Vias Neurais/fisiologia , Nicotina/farmacologia , Piridinas/farmacologia , Quinuclidinas/administração & dosagem , Quinuclidinas/farmacologia , Ratos , Transdução de Sinais , Núcleo Solitário/metabolismo , Taquicardia/induzido quimicamente , Taquicardia/prevenção & controleRESUMO
Chronic effects of a combination antiretroviral therapy (cART = tenofovir/emtricitatine + atazanavir/ritonavir) on systemic and cardiac oxidative stress/injury in HIV-1 transgenic (Tg) rats and protection by Mg-supplementation were assessed. cART (low doses) elicited no significant effects in normal rats, but induced time-dependent oxidative/nitrosative stresses: 2.64-fold increased plasma 8-isoprostane, 2.0-fold higher RBC oxidized glutathione (GSSG), 3.2-fold increased plasma 3-nitrotyrosine (NT), and 3-fold elevated basal neutrophil superoxide activity in Tg rats. Increased NT staining occurred within cART-treated HIV-Tg hearts, and significant decreases in cardiac systolic and diastolic contractile function occurred at 12 and 18 weeks. HIV-1 expression alone caused modest levels of oxidative stress and cardiac dysfunction. Significantly, cART caused up to 24% decreases in circulating Mg in HIV-1-Tg rats, associated with elevated renal NT staining, increased creatinine and urea levels, and elevated plasma substance P levels. Strikingly, Mg-supplementation (6-fold) suppressed all oxidative/nitrosative stress indices in the blood, heart and kidney and substantially attenuated contractile dysfunction (>75%) of cART-treated Tg rats. In conclusion, cART caused significant renal and cardiac oxidative/nitrosative stress/injury in Tg-rats, leading to renal Mg wasting and hypomagnesemia, triggering substance P-dependent neurogenic inflammation and cardiac dysfunction. These events were effectively attenuated by Mg-supplementation likely due to its substance P-suppressing and Mg's intrinsic anti-peroxidative/anti-calcium properties.
Assuntos
Antirretrovirais/efeitos adversos , Coração/efeitos dos fármacos , Magnésio/uso terapêutico , Inflamação Neurogênica/induzido quimicamente , Inflamação Neurogênica/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Animais , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Cardiotoxinas/efeitos adversos , Expressão Gênica , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/genética , Coração/fisiopatologia , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , Inflamação Neurogênica/fisiopatologia , Ativação de Neutrófilo/efeitos dos fármacos , Estresse Nitrosativo/efeitos dos fármacos , Ratos Endogâmicos F344 , Ratos TransgênicosRESUMO
BACKGROUND AND PURPOSE: Based on the fact that traumatic brain injury is associated with mitochondrial dysfunction we aimed at localization of mitochondrial defect and attempted to correct it by thiamine. EXPERIMENTAL APPROACH: Interventional controlled experimental animal study was used. Adult male Sprague-Dawley rats were subjected to lateral fluid percussion traumatic brain injury. Thiamine was administered 1â¯h prior to trauma; cortex was extracted for analysis 4â¯h and 3â¯d after trauma. KEY RESULTS: Increased expression of inducible nitric oxide synthase (iNOS) and tumor necrosis factor receptor 1 (TNF-R1) by 4â¯h was accompanied by a decrease in mitochondrial respiration with glutamate but neither with pyruvate nor succinate. Assays of TCA cycle flux-limiting 2-oxoglutarate dehydrogenase complex (OGDHC) and functionally linked enzymes (glutamate dehydrogenase, glutamine synthetase, pyruvate dehydrogenase, malate dehydrogenase and malic enzyme) indicated that only OGDHC activity was decreased. Application of the OGDHC coenzyme precursor thiamine rescued the activity of OGDHC and restored mitochondrial respiration. These effects were not mediated by changes in the expression of the OGDHC sub-units (E1k and E3), suggesting post-translational mechanism of thiamine effects. By the third day after TBI, thiamine treatment also decreased expression of TNF-R1. Specific markers of unfolded protein response did not change in response to thiamine. CONCLUSION AND IMPLICATIONS: Our data point to OGDHC as a major site of damage in mitochondria upon traumatic brain injury, which is associated with neuroinflammation and can be corrected by thiamine. Further studies are required to evaluate the pathological impact of these findings in clinical settings.
Assuntos
Biomarcadores/metabolismo , Lesões Encefálicas Traumáticas/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Complexo Cetoglutarato Desidrogenase/metabolismo , Mitocôndrias/fisiologia , Inflamação Neurogênica/prevenção & controle , Tiamina/farmacologia , Animais , Metabolismo Energético , Complexo Cetoglutarato Desidrogenase/antagonistas & inibidores , Complexo Cetoglutarato Desidrogenase/genética , Masculino , Mitocôndrias/efeitos dos fármacos , Inflamação Neurogênica/etiologia , Inflamação Neurogênica/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Oxirredução , Ratos , Ratos Sprague-Dawley , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Complexo Vitamínico B/farmacologiaRESUMO
Neurotropin (NTP) is a widely used drug in China and Japan mainly for the treatment of chronic pain and peripheral inflammation. Nevertheless, the effects of NTP on neuroinflammation have not been explored. In this study, we investigated the anti-inflammatory effects of NTP in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and its underlying mechanisms. BV-2 cells were pretreated with NTP for 12 h before exposure to LPS. The expression of pro-inflammatory cytokines (TNF-α and IL-6) were detected by RT-PCR and EILSA at mRNA and protein levels, respectively. Western blotting was conducted to measure the protein levels of major genes in MAPKs and NF-κB signaling pathways. Results demonstrated that NTP could attenuate the production of pro-inflammatory cytokines. Furthermore, NTP inhibited the activation of NF-κB signaling by decreasing the translocation of NF-κB p65 to the nucleus and suppressed the MAPKs signaling pathway via inhibition of the phosphorylation of p38, ERK and JNK. Taken together, these findings suggest that neurotropin exerts anti-inflammatory effects by suppressing the production of pro-inflammatory mediators via inhibition of NF-κB and MAPKs signaling pathways in LPS-stimulated BV-2 cells.
Assuntos
Lipopolissacarídeos/efeitos adversos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Microglia/patologia , NF-kappa B/metabolismo , Inflamação Neurogênica/induzido quimicamente , Inflamação Neurogênica/prevenção & controle , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Animais , Anti-Inflamatórios , Células Cultivadas , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-6/metabolismo , Camundongos , Inflamação Neurogênica/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The neurological changes elicited by bacterial infection are called sickness behavior. Minocycline (MIN) is neuroprotective with a remarkable brain tissue penetration. MIN was orally administered at a dose 90 mg/kg for 3 days, whereas Escherichia coli was given as a single intraperitoneal injection (0.2 mL of 24 h growth) on the third day. After 24 h of bacterial infection, behavioral tests namely open field and forced swimming were carried out, then animals were decapitated. Rats infected with E. coli displayed reduced struggling time in forced swimming test, as well as, exploration and locomotion in open field test with reduction in neurotransmitters (norepinephrine, dopamine, and serotonin) versus elevation in the inflammatory (tumor necrosis factor-alpha, interferon-gamma) and oxidative stress (thiobarbituric acid reactive substance, reduced glutathione) biomarkers. Inflammatory infiltrates of nuclear cells were observed in brains of infected rats. MIN administration prevented the deleterious effects of E. coli infection, thus protects against sickness behavior possibly via defending from neuroinflammation.
Assuntos
Antibacterianos/uso terapêutico , Encéfalo/efeitos dos fármacos , Infecções por Escherichia coli/tratamento farmacológico , Minociclina/uso terapêutico , Inflamação Neurogênica/prevenção & controle , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Animais , Antibacterianos/efeitos adversos , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Biomarcadores/metabolismo , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Química Encefálica/efeitos dos fármacos , Citocinas/metabolismo , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/imunologia , Infecções por Escherichia coli/metabolismo , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/fisiopatologia , Glutationa/química , Glutationa/metabolismo , Comportamento de Doença/efeitos dos fármacos , Masculino , Minociclina/efeitos adversos , Inflamação Neurogênica/etiologia , Inflamação Neurogênica/imunologia , Inflamação Neurogênica/patologia , Neurônios/imunologia , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/efeitos adversos , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-DawleyRESUMO
PURPOSE: Depression is frequently associated with inflammation, whereas omega-3 polyunsaturated fatty acids (PUFAs) primarily found in fish oil possess anti-inflammatory properties. Although converging studies suggest an antidepressant effect of PUFAs, there is limited evidence directly linking the neuro-immune modulating features of PUFAs to the antidepressant actions. METHODS: Therefore, we assessed the effects of fish oil (FO) supplementation on behavioral changes, inflammatory cytokine expression and oxidative reactions in frontal cortex and hippocampus of rats following repeated peripheral immune challenge by lipopolysaccharide (LPS) for 2 weeks (500 µg/kg every other day). RESULTS: Repeated LPS administration induced the rats to a depressive-like state and increased mRNA expression of pro-inflammatory cytokines, including 1L-1ß, 1L-6 and TNF-α, in frontal cortex and hippocampus. FO supplementation attenuated the LPS-induced abnormal behavior and brain inflammatory response. Concurrent with the antidepressant action, FO also reduced LPS-induced oxidative reactions and neural apoptosis in the rat brain, as evidenced by decreased malondialdehyde (MDA) production, increased catalase activities and inhibited pro-apoptotic protein Bax mRNA expression. In addition, FO inhibited activation of NF-κB and iNOS induced by LPS. Interestingly, we found FO suppressed the activation of the inflammasome NLRP3 and ionotropic purinergic receptor P2X7R evoked by LPS, suggesting a potential anti-inflammatory mechanism for PUFAs. Besides, FO also restored the LPS-induced neurochemical disturbance, especially the balance between serotonin and kynurenine branches of tryptophan metabolism, which is tightly associated with depression. CONCLUSIONS: These findings provide novel insights into the antidepressant action of PUFAs and further strengthen the link between inflammation and depression.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Depressão/prevenção & controle , Suplementos Nutricionais , Óleos de Peixe/uso terapêutico , Hipocampo/imunologia , Inflamação Neurogênica/prevenção & controle , Córtex Pré-Frontal/imunologia , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Antidepressivos/efeitos adversos , Antidepressivos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Biomarcadores/metabolismo , Citocinas/genética , Citocinas/metabolismo , Depressão/etiologia , Depressão/metabolismo , Suplementos Nutricionais/efeitos adversos , Óleos de Peixe/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Lipopolissacarídeos/toxicidade , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Inflamação Neurogênica/imunologia , Inflamação Neurogênica/patologia , Inflamação Neurogênica/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/imunologia , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/uso terapêutico , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Distribuição Aleatória , Ratos Sprague-Dawley , Receptores Purinérgicos P2X7/genética , Receptores Purinérgicos P2X7/metabolismoRESUMO
Epilepsy can be a devastating disorder. In addition to debilitating seizures, epilepsy can cause cognitive and emotional problems with reduced quality of life. Therefore, the major aim is to prevent the disorder in the first place: identify, detect, and reverse the processes responsible for its onset, and monitor and treat its progression. Epilepsy often occurs following a latent period of months to years (epileptogenesis) as a consequence of a brain insult, such as head trauma, stroke, or status epilepticus. Although this latent period clearly represents a therapeutic window, we are not able to stratify patients at risk for long-term epilepsy, which is prerequisite for preventative clinical trials. Moreover, because of the length of the latent period, an early biomarker for treatment response would be of high value. Finally, mechanistic biomarkers of epileptogenesis may provide more profound insight in the process of disease development.
Assuntos
Biomarcadores/análise , Epilepsia/imunologia , Inflamação Neurogênica/imunologia , Animais , Astrócitos/fisiologia , Encéfalo/diagnóstico por imagem , Encéfalo/imunologia , Encéfalo/fisiopatologia , Lesões Encefálicas/complicações , Lesões Encefálicas/diagnóstico por imagem , Lesões Encefálicas/imunologia , Lesões Encefálicas/fisiopatologia , Modelos Animais de Doenças , Progressão da Doença , Eletroencefalografia , Epilepsia/diagnóstico por imagem , Epilepsia/fisiopatologia , Epilepsia/prevenção & controle , Humanos , Aumento da Imagem , Imageamento por Ressonância Magnética , Inflamação Neurogênica/diagnóstico por imagem , Inflamação Neurogênica/fisiopatologia , Inflamação Neurogênica/prevenção & controle , Espectroscopia de Prótons por Ressonância Magnética , Ratos , Fatores de Risco , Convulsões Febris/diagnóstico por imagem , Convulsões Febris/fisiopatologia , Estado Epiléptico/complicações , Estado Epiléptico/diagnóstico por imagem , Estado Epiléptico/imunologia , Estado Epiléptico/fisiopatologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/fisiopatologia , Molécula 1 de Adesão de Célula Vascular/análise , Gravação em VídeoRESUMO
(-)-ß-caryophyllene (BCP), a cannabinoid receptor type 2 (CB2)-selective phytocannabinoid, has already been shown in precedent literature to exhibit both anti-inflammatory and analgesic effects in mouse models of inflammatory and neuropathic pain. Herein, we endeavored to investigate the therapeutic potential of BCP on experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). Furthermore, we sought to demonstrate some of the mechanisms that underlie the modulation BCP exerts on autoimmune activated T cells, the pro-inflammatory scenery of the central nervous system (CNS), and demyelination. Our findings demonstrate that BCP significantly ameliorates both the clinical and pathological parameters of EAE. In addition, data hereby presented indicates that mechanisms underlying BCP immunomodulatory effect seems to be linked to its ability to inhibit microglial cells, CD4+ and CD8+ T lymphocytes, as well as protein expression of pro-inflammatory cytokines. Furthermore, it diminished axonal demyelination and modulated Th1/Treg immune balance through the activation of CB2 receptor. Altogether, our study represents significant implications for clinical research and strongly supports the effectiveness of BCP as a novel molecule to target in the development of effective therapeutic agents for MS.
Assuntos
Encefalomielite Autoimune Experimental/prevenção & controle , Inflamação Neurogênica/prevenção & controle , Paralisia/prevenção & controle , Receptor CB2 de Canabinoide/metabolismo , Sesquiterpenos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Citocinas/metabolismo , Doenças Desmielinizantes/prevenção & controle , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/fisiopatologia , Feminino , Humanos , Hiperalgesia/prevenção & controle , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Esclerose Múltipla/metabolismo , Esclerose Múltipla/fisiopatologia , Esclerose Múltipla/prevenção & controle , Inflamação Neurogênica/metabolismo , Inflamação Neurogênica/fisiopatologia , Paralisia/metabolismo , Paralisia/fisiopatologia , Sesquiterpenos Policíclicos , Receptor CB2 de Canabinoide/agonistas , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismoRESUMO
Neurotrophins (NTs) have been implicated in generation and modulation of nociceptive pathways. Change in NTs levels is associated with painful conditions and neurological diseases such as migraine. Currently, it is generally recognized that migraine headaches result from the activation and sensitization of trigeminal sensory afferent fibers leading to neuropeptides release such as calcitonin gene-related peptide (CGRP) and substance P (SP). This triggers an inflammatory cascade causing a neurogenic inflammation. The agents responsible for trigeminal activation and release of neuropeptides are still unclear. It is known that the transient receptor potential vanilloid receptor-1 (TRPV1) is an important mediator of CGRP and SP release. TRPV1 is closely associated with tyrosine receptors kinases (Trk), which are NTs receptors. NTs can act on TRPV1 increasing its sensitivity to painful stimuli, therefore predisposing to hyperalgesia. Upregulation of ion channels and pain receptors in dorsal root ganglion neurons may be alternative mechanisms by which NTs contribute to pain development. Only a few studies have been performed to investigate the role of NTs in migraine. These studies have reported changes in NTs levels in migraine patients either during the migraine attack or in free-headache periods.
Assuntos
Encéfalo/metabolismo , Transtornos de Enxaqueca/metabolismo , Modelos Neurológicos , Fatores de Crescimento Neural/metabolismo , Neurônios/metabolismo , Receptores de Fator de Crescimento Neural/agonistas , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/imunologia , Gânglios Espinais/metabolismo , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/imunologia , Transtornos de Enxaqueca/fisiopatologia , Fatores de Crescimento Neural/antagonistas & inibidores , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/metabolismo , Inflamação Neurogênica/etiologia , Inflamação Neurogênica/prevenção & controle , Neurônios/efeitos dos fármacos , Neurônios/imunologia , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/imunologia , Neurônios Aferentes/metabolismo , Dor Nociceptiva/etiologia , Dor Nociceptiva/prevenção & controle , Receptores de Fator de Crescimento Neural/antagonistas & inibidores , Receptores de Fator de Crescimento Neural/metabolismo , Transdução de Sinais/efeitos dos fármacos , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismoRESUMO
OBJECTIVES: Acute peripheral infection is associated with central and peripheral inflammation, increased oxidative stress, and adaptive sickness behaviors. Sulforaphane (SFN) activates the transcription factor nuclear factor E2-related factor 2 (Nrf2), which upregulates antioxidant genes and lowers inflammation. The objectives of this study were to examine the effects of SFN on proinflammatory markers and Nrf2 target genes in hippocampus and liver of mice challenged with lipopolysaccharide (LPS), and to evaluate sickness response following the LPS immune challenge. METHODS: Adult Balb/c mice received SFN (50â mg/kg, i.p.) for 3 days before being injected i.p. with LPS (1â µg) to mimic an acute peripheral infection. Sickness behaviors were measured at baseline and 6 hours after LPS. Expression of proinflammatory mediators and antioxidant genes were analyzed in hippocampus and liver 6 hours after LPS. RESULTS: SFN elevated Nrf2 target genes and reduced expression of proinflammatory mediators in hippocampus and liver, but did not improve LPS-induced sickness response. DISCUSSION: The nutritional bioactive SFN displays potent anti-inflammatory properties against LPS-induced inflammation in vitro, but has not been previously assessed in vivo during peripheral infection as a potential treatment for sickness behavior. These data indicate that SFN has anti-inflammatory effects in both brain and periphery, but that longer exposure to SFN may be necessary to reduce sickness behavior.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Mediadores da Inflamação/antagonistas & inibidores , Isotiocianatos/uso terapêutico , Inflamação Neurogênica/prevenção & controle , Neurônios/efeitos dos fármacos , Animais , Anticarcinógenos/uso terapêutico , Elementos de Resposta Antioxidante/efeitos dos fármacos , Antioxidantes/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Biomarcadores/metabolismo , Endotoxinas/toxicidade , Ingestão de Energia/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/imunologia , Hipocampo/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/imunologia , Hipotálamo/metabolismo , Mediadores da Inflamação/metabolismo , Injeções Intraperitoneais , Isotiocianatos/administração & dosagem , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/inervação , Fígado/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Inflamação Neurogênica/imunologia , Neurônios/imunologia , Neurônios/metabolismo , Especificidade de Órgãos , SulfóxidosRESUMO
Stress occurs in everyday life and persistence of it causes memory loss. Bioflavonoids like quercetin are reported to have poor bioavailability and limited therapeutic potential against stress induced neurological disorders. Therefore, the present study is an attempt to elucidate the therapeutic potency of combination of quercetin with piperine; a bioavailability enhancer against chronic unpredictable stress (CUS)-induced behavioral and biochemical alterations. Laca mice were subjected to a series of stressful events for a period of 28 days. Quercetin (20, 40 and 80 mg/kg, p.o.), piperine (20 mg/kg, p.o.) and their combinations were administered daily 30 min before CUS procedure. Piracetam (100 mg/kg, i.p.) served as a standard control. CUS caused impaired spatial navigation in Morris water maze test and poor retention in elevated plus maze task. Further, there was significant increase in brain oxidative stress markers and neuro-inflammation (TNF-α). This was coupled with marked rise in acetylcholinesterase and serum corticosterone levels. Co-administration of piperine with quercetin significantly elevated their potential to restore these behavioral, biochemical and molecular changes associated with mouse model of CUS. These results suggest that piperine enhances the neuroprotective effects of quercetin against CUS-induced oxidative stress, neuro-inflammation and memory deficits.
Assuntos
Alcaloides/uso terapêutico , Benzodioxóis/uso terapêutico , Disfunção Cognitiva/prevenção & controle , Inflamação Neurogênica/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/uso terapêutico , Alcamidas Poli-Insaturadas/uso terapêutico , Quercetina/uso terapêutico , Estresse Psicológico/tratamento farmacológico , Alcaloides/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Benzodioxóis/administração & dosagem , Disponibilidade Biológica , Doença Crônica , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Masculino , Camundongos Endogâmicos , Piperidinas/administração & dosagem , Alcamidas Poli-Insaturadas/administração & dosagem , Quercetina/administração & dosagem , Estresse Psicológico/imunologia , Estresse Psicológico/metabolismoRESUMO
Chronic neuro-inflammation is involved in the death of retinal ganglion cells (RGCs) in glaucoma. The aim of this study is to determine whether wogonin can suppress inflammatory responses and rescue RGCs death after optic nerve crush (ONC), an ideal animal model of glaucoma. Wogonin was administered intraperitoneally 10 min after establishment of ONC model. In this study, wogonin treatment reduced RGCs loss and inhibited RGCs apoptosis demonstrated by the increased Brn3a labeling RGCs at day 14 and the decreased cleaved caspase-3 expression at day 7 after ONC, respectively. In ONC model, number of GFAP-positive glial cells and iba1-positive microglial cells were increased, combined of the elevated level of pro-inflammatory cytokines released in retina at day 7. However, most of these responses were inhibited after wogonin treatment. The level of TLR4 expression, NF-κB-P65 nucleus location and NF-κB-P65 phosphorylation were increased in retina at day 1 after ONC, which was significantly reduced after wogonin treatment. These results demonstrated that wogonin protected RGCs survival and suppressed neuro-inflammation in retina after ONC by inhibiting TLR4-NF-κB pathways. We conclude that wogonin could be a possible strategy for the treatment of glaucoma.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Flavanonas/farmacologia , Inflamação Neurogênica/prevenção & controle , Nervo Óptico/patologia , Células Ganglionares da Retina/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Glaucoma/metabolismo , Glaucoma/patologia , Masculino , NF-kappa B/metabolismo , Compressão Nervosa , Inflamação Neurogênica/metabolismo , Inflamação Neurogênica/patologia , Nervo Óptico/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Células Ganglionares da Retina/citologia , Células Ganglionares da Retina/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
The role of inflammation in neurological disorders is increasingly recognised. Inflammatory processes are associated with the aetiology and clinical progression of migraine, psychiatric conditions, epilepsy, cerebrovascular diseases, dementia and neurodegeneration, such as seen in Alzheimer's or Parkinson's disease. Both central and systemic inflammatory actions have been linked with the development of brain diseases, suggesting that complex neuro-immune interactions could contribute to pathological changes in the brain across multiple temporal and spatial scales. However, the mechanisms through which inflammation impacts on neurological disease are improperly defined. To develop effective therapeutic approaches, it is imperative to understand how detrimental inflammatory processes could be blocked selectively, or controlled for prolonged periods, without compromising essential immune defence mechanisms. Increasing evidence indicates that common risk factors for brain disorders, such as atherosclerosis, diabetes, hypertension, obesity or infection involve the activation of NLRP3, NLRP1, NLRC4 or AIM2 inflammasomes, which are also associated with various neurological diseases. This review focuses on the mechanisms whereby inflammasomes, which integrate diverse inflammatory signals in response to pathogen-driven stimuli, tissue injury or metabolic alterations in multiple cell types and different organs of the body, could functionally link vascular- and neurological diseases and hence represent a promising therapeutic target.
Assuntos
Encefalopatias/imunologia , Inflamassomos/imunologia , Inflamação Neurogênica/imunologia , Doenças Vasculares/imunologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/uso terapêutico , Encefalopatias/patologia , Encefalopatias/prevenção & controle , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inflamassomos/efeitos dos fármacos , Inflamação Neurogênica/patologia , Inflamação Neurogênica/prevenção & controle , Doenças Vasculares/patologia , Doenças Vasculares/prevenção & controleRESUMO
Postoperative cognitive dysfunction (POCD) is a significant cause of morbidity after surgery, especially for the elderly. Accumulating evidence has demonstrated that neuroinflammation plays a key role in the pathogenesis of POCD. Thus, we hypothesized that berberine, an isoquinoline alkaloid with anti-inflammatory effects, could improve surgery-induced cognitive impairment. Twenty-month-old male C57BL/6 mice were subjected to exploratory laparotomy with isoflurane anesthesia to mimic the clinical human abdominal surgery. For the interventional studies, mice received berberine (10mg/kg) or vehicle intraperitoneally. For the in vitro study, we examined the effects of berberine on lipopolysaccharide (LPS)-induced inflammatory mediators by cultured BV2 cells. Behavioral tests, expressions of IBA1, tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6 were performed at the indicated time points. In the present study, we showed that surgery impaired the contextual fear memory, as evidenced by the significantly decreased freezing time to the context. This behavioral change coincided with marked increases in IBA1, TNF-α, IL-1ß, and IL-6 in the prefrontal cortex and hippocampus only at 24h but not 7 d after surgery. In BV2 cells, LPS induced significantly increased TNF-α and IL-1ß expressions. Notably, berberine treatment rescued surgery-induced cognitive impairment and inhibited the release of IBA1, IL-1ß, and IL-6 in the hippocampus. In line with the in vivo study, berberine treatment suppressed LPS-stimulated production of TNF-α and IL-1ß in BV2 cells. In conclusion, our study suggests that berberine could alleviate POCD by suppressing neuroinflammation in aged mice.
Assuntos
Envelhecimento/fisiologia , Anti-Inflamatórios/uso terapêutico , Berberina/uso terapêutico , Disfunção Cognitiva/prevenção & controle , Hipocampo/efeitos dos fármacos , Laparotomia , Microglia/efeitos dos fármacos , Inflamação Neurogênica/prevenção & controle , Complicações Pós-Operatórias/prevenção & controle , Idoso , Animais , Proteínas de Ligação ao Cálcio , Linhagem Celular , Disfunção Cognitiva/etiologia , Citocinas/metabolismo , Hipocampo/imunologia , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos , Microglia/fisiologia , Modelos Animais , Inflamação Neurogênica/etiologiaRESUMO
BACKGROUND: Triptans are agonists to 5-HT 1B/D/F receptors, which are present on nociceptive neurons not only within but also beyond the trigeminal system. The aim of this study was to investigate whether zolmitriptan interacts with peptidergic nociceptive afferents in human skin. METHODS: Twenty participants (13 women, median age: 25; interquartile range: 23-26 years) entered the randomized, double-blind, cross-over study. Electrically induced neurogenic flare and pain was assessed after either placebo or zolmitriptan on the ventral thigh. Mechanical pain thresholds were investigated at baseline and after electrical stimulation at the stimulation site. RESULTS: The size of the neurogenic flare (F = 10.9; p = 0.002) as well as electrically induced pain were significantly reduced by zolmitriptan (F = 4.46; p = 0.041). Moreover, electrically induced pinprick hyperalgesia was significantly decreased by zolmitriptan compared with placebo (F = 6.243; p = 0.017). CONCLUSIONS: Triptans may have effects outside of the trigeminal system and reduce electrically evoked neurogenic inflammation and pain in human skin.
Assuntos
Inflamação Neurogênica/prevenção & controle , Oxazolidinonas/farmacologia , Dor/prevenção & controle , Agonistas do Receptor de Serotonina/farmacologia , Pele , Triptaminas/farmacologia , Adulto , Estudos Cross-Over , Método Duplo-Cego , Estimulação Elétrica , Feminino , Humanos , Masculino , Transtornos de Enxaqueca/tratamento farmacológico , Neurônios Aferentes/efeitos dos fármacos , Nociceptores/efeitos dos fármacos , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Estimulação Física , Adulto JovemRESUMO
Sickle cell anemia (SCA) is an inherited disorder associated with severe lifelong pain and significant morbidity. The mechanisms of pain in SCA remain poorly understood. We show that mast cell activation/degranulation contributes to sickle pain pathophysiology by promoting neurogenic inflammation and nociceptor activation via the release of substance P in the skin and dorsal root ganglion. Mast cell inhibition with imatinib ameliorated cytokine release from skin biopsies and led to a correlative decrease in granulocyte-macrophage colony-stimulating factor and white blood cells in transgenic sickle mice. Targeting mast cells by genetic mutation or pharmacologic inhibition with imatinib ameliorates tonic hyperalgesia and prevents hypoxia/reoxygenation-induced hyperalgesia in sickle mice. Pretreatment with the mast cell stabilizer cromolyn sodium improved analgesia following low doses of morphine that were otherwise ineffective. Mast cell activation therefore underlies sickle pathophysiology leading to inflammation, vascular dysfunction, pain, and requirement for high doses of morphine. Pharmacological targeting of mast cells with imatinib may be a suitable approach to address pain and perhaps treat SCA.
Assuntos
Anemia Falciforme/fisiopatologia , Mastócitos/fisiologia , Dor/fisiopatologia , Anemia Falciforme/sangue , Anemia Falciforme/genética , Animais , Benzamidas/farmacologia , Células Cultivadas , Citocinas/metabolismo , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Gânglios Espinais/fisiopatologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Hiperalgesia/genética , Hiperalgesia/fisiopatologia , Hipóxia/fisiopatologia , Mesilato de Imatinib , Contagem de Leucócitos , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microscopia Confocal , Inflamação Neurogênica/genética , Inflamação Neurogênica/fisiopatologia , Inflamação Neurogênica/prevenção & controle , Nociceptores/efeitos dos fármacos , Nociceptores/metabolismo , Nociceptores/fisiologia , Dor/genética , Dor/prevenção & controle , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pele/metabolismo , Pele/patologia , Pele/fisiopatologia , Substância P/metabolismoRESUMO
CONTEXT: Despite several pharmacological applications of Rosmarinus officinalis L. (Lamiaceae), studies on its analgesic and anti-inflammatory properties have been scarce. OBJECTIVE: The aim of this work was to use in vivo models to evaluate the analgesic and anti-inflammatory activities of the aqueous extracts obtained from leaves (AEL) and stems (AES) of Rosmarinus officinalis, as well as its isolated compound--rosmarinic acid (RA). We also prepared and assessed the acetyl ester derivative of RA. MATERIALS AND METHODS: The analgesic activity was evaluated using abdominal constriction and formalin tests. For the evaluation of the anti-inflammatory effects, carrageenin-induced paw edema in rats were used. The extracts were used at doses of 100, 200 and 400 mg kg⻹ compounds were tested at 10, 20 and 40 mg kg⻹. RESULTS: Orally administered AEL, AES and RA were not significantly active at any of the doses tested during the abdominal constriction test; the acetyl ester derivative of RA displayed significant analgesic activity. In the carrageenin-induced paw edema assay, the acetyl derivative of RA at all the tested doses produced significant anti-inflammatory effects and reduced the number of paw licks in the second phase of the formalin test. DISCUSSION AND CONCLUSION: The results suggest that the analgesic effects of the acetyl derivative of RA operate via a peripheral-mediated mechanism. The acetyl ester derivative of RA is potentially applicable as a new lead compound for the management of pain and inflammation.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Cinamatos/uso terapêutico , Depsídeos/uso terapêutico , Modelos Animais de Doenças , Neuralgia/prevenção & controle , Inflamação Neurogênica/prevenção & controle , Extratos Vegetais/uso terapêutico , Rosmarinus/química , Acetilação , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/isolamento & purificação , Comportamento Animal/efeitos dos fármacos , Brasil , Cinamatos/administração & dosagem , Cinamatos/química , Cinamatos/isolamento & purificação , Depsídeos/administração & dosagem , Depsídeos/química , Depsídeos/isolamento & purificação , Relação Dose-Resposta a Droga , Etnofarmacologia , Masculino , Medicina Tradicional , Camundongos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Caules de Planta/química , Ratos , Ratos Wistar , Ácido RosmarínicoRESUMO
Neuroinflammation driven by the vanilloid-type ion channel receptor transient receptor potential vanilloid type 1 (TRPV-1) is suspected to play a role in the pathophysiology of inflammatory bowel disease. Because inflammatory bowel disease is known to elevate the risk of colon cancer, we examined postulated roles for TRPV-1-driven neuroinflammation in promoting colitis-associated and spontaneous colon cancer development. Using a well-established model of colitis-associated cancer (CAC), we found that mice genetically deficient in TRPV-1 showed a higher incidence and number of tumors in the distal colon. In like manner, genetic deficiency of TRPV-1 in the APC(Min/+) model of spontaneous colon cancer accentuated the number of colonic adenomas formed. Mechanistic analyses in the CAC model revealed an increased infiltration of inflammatory cells into the tumors along with elevated expression of interleukin (IL)-6 and IL-11 and activation of the STAT3 and NF-κB signaling pathways. Notably, TPRV-1-deficient mice exhibited a defect in expression of the anti-inflammatory neuropeptides, vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP) which contributed to the generation of a local proinflammatory environment. Together, our findings argue that by limiting neuroinflammatory processes, TRPV-1 exerts a protective role that restricts the initiation and progression of colon cancer.