RESUMEN
Referred somatic pain triggered by hyperalgesia is common in patients with inflammatory bowel disease (IBD). It was reported that sprouting of sympathetic nerve fibers into the dorsal root ganglion (DGR) and neurogenic inflammation were related to neuropathic pain, the excitability of neurons, and afferents. The purpose of the study was to explore the potential and mechanism of electroacupuncture (EA) at Zusanli (ST36) for the intervention of colon inflammation and hyperalgesia. Sprague-Dawley (SD) was randomly divided into four groups, including control, model, EA, and sham-EA. Our results showed EA treatment significantly attenuated dextran sulfate sodium- (DSS-) induced colorectal lesions and inflammatory cytokine secretion, such as TNF-α, IL-1ß, PGE2, and IL-6. EA also inhibited mechanical and thermal pain hypersensitivities of colitis rats. Importantly, EA effectively abrogated the promotion effect of DSS on ipsilateral lumbar 6 (L6) DRG sympathetic-sensory coupling, manifested as the sprouting of tyrosine hydroxylase- (TH-) positive sympathetic fibers into sensory neurons and colocalization of and calcitonin gene-related peptide (CGRP). Furthermore, EA at Zusanli (ST36) activated neurogenic inflammation, characterized by decreased expression of substance P (SP), hyaluronic acid (HA), bradykinin (BK), and prostacyclin (PGI2) in colitis rat skin tissues corresponding to the L6 DRG. Mechanically, EA treatment reduced the activation of the TRPV1/CGRP, ERK, and TLR4 signaling pathways in L6 DRG of colitis rats. Taken together, we presumed that EA treatment improved colon inflammation and hyperalgesia, potentially by suppressing the sprouting of sympathetic nerve fibers into the L6 DGR and neurogenic inflammation via deactivating the TRPV1/CGRP, ERK, and TLR4 signaling pathways.
Asunto(s)
Colitis , Electroacupuntura , Neuralgia , Dolor Nociceptivo , Ratas , Animales , Ratas Sprague-Dawley , Hiperalgesia/metabolismo , Electroacupuntura/métodos , Ganglios Espinales/metabolismo , Péptido Relacionado con Gen de Calcitonina/metabolismo , Inflamación Neurogénica/metabolismo , Receptor Toll-Like 4/metabolismo , Neuralgia/metabolismo , Dolor Nociceptivo/metabolismoRESUMEN
Purpose: Proton pump inhibitors, as the first-line drugs for treating gastroesophageal reflux disease (GERD), are unable to completely relieve patients' symptoms and patients are prone to recurrence after prolonged drug withdrawal. Thus, it is crucial to find herbal medicines as a complementary and alternative treatment. Hewei Jiangni granule (HWJNG) is a classical Chinese medicinal formula with clinical therapeutic effects on GERD, but its pharmacological mechanism of action remains unclear. This study aimed to explore and then verify the pharmacological mechanisms of HWJNG in GERD therapy. Methods: A network pharmacology approach was applied to explore and then verify the pharmacological mechanisms of HWJNG in GERD therapy. The active ingredients of HWJNG, as well as therapeutic targets of GERD were acquired from specialized databases. The "herb-ingredient-gene-target" network for HWJNG in GERD treatment was built. The protein-protein interaction (PPI) network was constructed to screen the core coincident targets. Then, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. The core targets and signaling pathways associated with the anti-neurogenic inflammatory effect were partially verified via experiments in vivo at molecular level. Results: In total, 179 chemical ingredients in HWJNG and 298 intersection targets between GERD and HWJNG were selected from databases. A large proportion of core targets and top signaling pathways were involved in neurogenic inflammation. HWJNG significantly alleviated pathological injuries of esophagus and reversed dilated intracellular spaces. Additionally, HWJNG markedly inhibited the excessive release of inflammatory cytokines such as interleukin (IL)-1ß, IL-6, tumor necrosis factor receptor (TNF-a), as well as regulated stimulation sensors including transient receptor potential vanilloid type 1 (TRPV1) and its related neuroinflammatory mediators in GERD mice. Conclusion: HWJNG is a promising therapeutic strategy for GERD treatment via regulation of multiple targets and pathways, its effects in alleviating neurogenic inflammation are especially acknowledged.
Asunto(s)
Medicamentos Herbarios Chinos , Reflujo Gastroesofágico , Animales , Antiinflamatorios/farmacología , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Reflujo Gastroesofágico/tratamiento farmacológico , Humanos , Medicina Tradicional China , Ratones , Simulación del Acoplamiento Molecular , Farmacología en Red , Inflamación NeurogénicaRESUMEN
The inflammatory response related to surgery is considered surgical inflammation. Most anesthetic agents directly or indirectly suppress the immune response. However, the intravenous anesthetics pentobarbital and ketamine were reported to inhibit the lipopolysaccharide-induced inflammatory response such as cytokines formation. Neurogenic inflammation is inflammation originating from the local release of inflammatory mediators, such as substance P (SP), by primary afferent neurons after noxious stimuli like surgery. Thus, in this study, we examined whether pentobarbital and ketamine suppress SP release from cultured dorsal root ganglion (DRG) neurons. DRG cells were dissected from male Wistar rats. Released SP was measured by radioimmunoassay. We demonstrated that higher concentrations of pentobarbital (100-1,000 µM) significantly inhibited capsaicin (100 nM)-induced, but not high K+ (50 mM)-induced, SP release from DRG cells, although a high concentration of ketamine (1 mM) did not. This study revealed that pentobarbital functions between the activation of vanilloid receptor subtype 1 (TRPV1) receptors, to which capsaicin selectively binds, and the opening of voltage-operated Ca2+ channels (VOCC) in the nerve endings. Therefore, the anti-inflammatory action of pentobarbital is mediated through different mechanisms than those of ketamine. Thus, the inhibitory effect of pentobarbital on SP release from peripheral terminals may protect against neurogenic inflammation after surgery.
Asunto(s)
Antiinflamatorios/uso terapéutico , Inflamación Neurogénica/tratamiento farmacológico , Pentobarbital/uso terapéutico , Nervios Periféricos/metabolismo , Sustancia P/metabolismo , Analgésicos/farmacología , Animales , Antiinflamatorios/farmacología , Canales de Calcio/metabolismo , Capsaicina/farmacología , Células Cultivadas , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Ketamina/farmacología , Masculino , Inflamación Neurogénica/metabolismo , Pentobarbital/farmacología , Nervios Periféricos/efectos de los fármacos , Ratas , Ratas Wistar , Fármacos del Sistema Sensorial/farmacología , Canales Catiónicos TRPV/metabolismoRESUMEN
Using rat and mouse models of neurogenic, ethanol-induced, and indometacin-induced damage to the gastric mucosa we demonstrated that course preventive treatment with flavonoid complex from aerial parts of Lychnis chalcedonica L. increased the resistance of gastric mucosa to ulcerogenic factors of different etiology. The gastroprotective effect of the phytocomplex in a dose range of 16-1600 µg/kg was comparable with that of the reference drug plantaglucide and was superior to that of the reference drugs eleutherococcus extract and methyluracil in the therapeutic doses. The antiulcerogenic activity of Lychnis chalcedonica flavonoid complex considerably exceeded activity of Lychnis chalcedonica L. extract demonstrated in our previous experiments.
Asunto(s)
Antiulcerosos/uso terapéutico , Extractos Vegetales/uso terapéutico , Úlcera Gástrica/tratamiento farmacológico , Animales , Animales no Consanguíneos , Antiulcerosos/aislamiento & purificación , Antiulcerosos/farmacología , Citoprotección/efectos de los fármacos , Modelos Animales de Enfermedad , Etanol , Flavonoides/aislamiento & purificación , Flavonoides/farmacología , Flavonoides/uso terapéutico , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/patología , Indometacina , Lychnis/química , Masculino , Ratones , Inflamación Neurogénica/tratamiento farmacológico , Inflamación Neurogénica/patología , Fitoterapia , Extractos Vegetales/farmacología , Ratas , Ratas Wistar , Silene , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/patologíaRESUMEN
Visceral pain frequently produces referred pain at somatic sites due to the convergence of somatic and visceral afferents. In skin overlying the referred pain, neurogenic spots characterized by hyperalgesia, tenderness and neurogenic inflammation are found. We investigated whether neurogenic inflammatory spots function as acupoints in the rat model of bile duct ligation-induced liver injury. The majority of neurogenic spots were found in the dorsal trunk overlying the referred pain and matched with locations of acupoints. The spots, as well as acupoints, showed high electrical conductance and enhanced expression of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP). Electroacupuncture at neurogenic spots reduced serum hepatocellular enzyme activities and histological patterns of acute liver injury in bile duct ligation (BDL) rats. The results suggest that the neurogenic spots have therapeutic effects as acupoints on hepatic injury in bile-duct ligated rats.
Asunto(s)
Conductos Biliares/patología , Electroacupuntura , Hígado/patología , Inflamación Neurogénica/terapia , Dolor Referido/terapia , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Conductividad Eléctrica , Hiperalgesia/complicaciones , Ligadura , Inflamación Neurogénica/complicaciones , Dolor Referido/complicaciones , Ratas Sprague-Dawley , Piel/patología , Sustancia P/metabolismoRESUMEN
OBJECTIVE: To observe the effect of intranasal acupuncture on allergic rhinitis (AR), and expression of substance P (SP), vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY) proteins in the nasal mucosa and contents of serum immunoglobulin E (IgE), interleukin 4 (IL-4) and interferon-γ (IFN-γ) in AR rabbits, so as to explore its mechanisms underlying improvement of AR. METHODS: New Zealand rabbits were randomly divided into normal control, AR model, non-acupuoint acupuncture (NAA) and intranasal acupuncture (INA) groups, with 8 rabbits in each group. The AR model was established by intra-peritoneal injection of egg protein and nasal mucosal stimulation. In the INA group, bilateral "Neiyingxiang" (EX-HN9) within the nasal cavity (the anterior attachment area of the inferior turbinate, about 1 cm away from the nasal limen) were acupunctured by mani-pulating the filiform needles for a while with uniform reinforcing and reducing methods, followed by keeping the needles for 20 min. In the NAA group, shallow acupuncture was applied to the skin of the outer margin of the cheeks, followed by keeping the needle for 20 min. The acupuncture treatment was conducted once every other day for 7 days. The symptoms of sneezing frequency, nasal secretion amount and nasal itching were scored. The expression levels of SP, VIP and NPY in the nasal mucosa tissue were detected by immunohistochemistry, and the serum IgE, IL-4, and IFN-γ contents were detected by ELISA. RESULTS: After modelling, the symptom score, expression of SP and VIP, and serum IgE and IL-4 contents were significantly higher (P<0.01,P<0.05), NPY expression and serum IFN-γ content significantly lower (P<0.05, P<0.01) in the model group than in the normal control group. Following the intervention, the symptom scores, expressions of SP and VIP, and serum IgE and IL-4 contents were remarkably decreased (P<0.05, P<0.01), while the NPY expression and serum IFN-γ content were significantly up-regulated (P<0.05, P<0.01) in the INA group than in the model group. The effects of INA group were significantly superior to those of NAA group in reducing symptom score, SP and VIP expression, and serum IgE and IL-4 contents and up-regulating NPY expression and IFN-γcontent (P<0.05, P<0.01). There were a positive correlation between the expressions of SP and VIP and contents of serum IgE and IL-4 (P<0.05), and a negative correlation between the expressions of SP and VIP and IFN-γ content (P<0.05). CONCLUSION: INA treatment can relieve symptoms of AR in AR rabbits, which may be associated with its effects in regulating the expression of SP, VIP and NPY of the nasal mucosa, and contents of serum IgE, IL-4 and IFN-γ to improve neurogenic inflammation.
Asunto(s)
Terapia por Acupuntura , Rinitis Alérgica , Animales , Inmunoglobulina E , Mucosa Nasal , Inflamación Neurogénica , Conejos , Rinitis Alérgica/genética , Rinitis Alérgica/terapiaRESUMEN
BACKGROUND: Chronic cerebral hypoperfusion (CCH) is regarded as a high-risk factor for cognitive decline in vascular dementia (VaD). We have previously shown that diabetes mellitus (DM) synergistically promotes CCH-induced cognitive dysfunction via exacerbating neuroinflammation. Furthermore, curcumin has been shown to exhibit anti-inflammatory and neuroprotective activities. However, the effects of curcumin on CCH-induced cognitive impairments in DM have remained unknown. METHODS: Rats were fed with a high-fat diet (HFD) and injected with low-dose streptozotocin (STZ), followed by bilateral common carotid artery occlusion (BCCAO), to model DM and CCH in vivo. After BCCAO, curcumin (50 mg/kg) was administered intraperitoneally every two days for eight weeks to evaluate its therapeutic effects. Additionally, mouse BV2 microglial cells were exposed to hypoxia and high glucose to model CCH and DM pathologies in vitro. RESULTS: Curcumin treatment significantly improved DM/CCH-induced cognitive deficits and attenuated neuronal cell death. Molecular analysis revealed that curcumin exerted protective effects via suppressing neuroinflammation induced by microglial activation, regulating the triggering receptor expressed on myeloid cells 2 (TREM2)/toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway, alleviating apoptosis, and reducing nod-like receptor protein 3 (NLRP3)-dependent pyroptosis. CONCLUSIONS: Taken together, our findings suggest that curcumin represents a promising therapy for DM/CCH-induced cognitive impairments.
Asunto(s)
Antiinflamatorios/uso terapéutico , Disfunción Cognitiva/prevención & control , Curcumina/uso terapéutico , Diabetes Mellitus/terapia , Hipoxia Encefálica/terapia , Microglía/fisiología , Animales , Apoptosis , Células Cultivadas , Disfunción Cognitiva/etiología , Modelos Animales de Enfermedad , Humanos , Hipoxia Encefálica/complicaciones , Masculino , Ratones , Inflamación Neurogénica , Piroptosis , Ratas , Ratas Sprague-DawleyRESUMEN
Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS). The persistent inflammation is being mainly attributed to local oxidative stress and inflammasome activation implicated in the ensuing demyelination and axonal damage. Since new control measures remain necessary, we evaluated the preventive and therapeutic potential of a beta-selenium-lactic acid derivative (LAD-ßSe), which is a source of organic selenium under development, to control experimental autoimmune encephalomyelitis (EAE) that is an animal model for MS. Two EAE murine models: C57BL/6 and SJL/J immunized with myelin oligodendrocyte glycoprotein and proteolipid protein, respectively, and a model of neurodegeneration induced by LPS in male C57BL/6 mice were used. The preventive potential of LAD-ßSe was initially tested in C57BL/6 mice, the chronic MS model, by three different protocols that were started 14 days before or 1 or 7 days after EAE induction and were extended until the acute disease phase. These three procedures were denominated preventive therapy -14 days, 1 day, and 7 days, respectively. LAD-ßSe administration significantly controlled clinical EAE development without triggering overt hepatic and renal dysfunction. In addition of a tolerogenic profile in dendritic cells from the mesenteric lymph nodes, LAD-ßSe also downregulated cell amount, activation status of macrophages and microglia, NLRP3 (NOD-like receptors) inflammasome activation and other pro-inflammatory parameters in the CNS. The high Se levels found in the CNS suggested that the product crossed the blood-brain barrier having a possible local effect. The hypothesis that LAD-ßSe was acting locally was then confirmed by using the LPS-induced neurodegeneration model that also displayed Se accumulation and downmodulation of pro-inflammatory parameters in the CNS. Remarkably, therapy with LAD-ßSe soon after the first remitting episode in SJL/J mice, also significantly downmodulated local inflammation and clinical disease severity. This study indicates that LAD-ßSe, and possibly other derivatives containing Se, are able to reach the CNS and have the potential to be used as preventive and therapeutic measures in distinct clinical forms of MS.
Asunto(s)
Antiinflamatorios/uso terapéutico , Sistema Nervioso Central/efectos de los fármacos , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Inflamasomas/metabolismo , Microglía/patología , Esclerosis Múltiple/tratamiento farmacológico , Inflamación Neurogénica/tratamiento farmacológico , Selenio/uso terapéutico , Animales , Sistema Nervioso Central/patología , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/inmunología , Humanos , Ácido Láctico/química , Masculino , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/inmunología , Glicoproteína Mielina-Oligodendrócito/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Inflamación Neurogénica/inmunología , Selenio/químicaRESUMEN
OBJECTIVE: To investigate the efficacy of active compounds of Chanqin (CQ) granules on PM2.5-induced airway neurogenic inflammation in vivo, and to elucidate the underlying mechanisms of action. METHODS: The Traditional Chinese Medicine systems pharmacology (TCMSP) database was searched, and the results were combined with oral bioavailability and drug analysis to identify the compounds in CQ granules. The pharmacophore modeling approach was used to predict the compound targets, and the diseases corresponding to the targets were obtained by searching the therapeutic target database (TTD), pharmacogenomics knowledgebase (PharmGKB) and DrugBank databases. Cytoscape software was used to construct the network pharmacological charts for Component-Target and Target-Disease interactions of the CQ granules. Then, the mechanisms of action and effectiveness of CQ granules for the treatment of PM2.5-induced airway neurogenic inflammation were analyzed. RESULTS: A total of 195 compounds and 171 targets were obtained from the analyses. A total of 569 corresponding diseases were identified for these targets. Component-target and target-disease networks were constructed. The possible mechanisms and effective components in CQ granules for treating airway neurogenic inflammation were analyzed. Quercetin, kaempferol and isorhamnetin, beta-sitosterol and sitosterol, which are typically found in the formulation, have extensive pharmacological activities, including anti-inflammatory, antioxidant and antiviral actions and neuroprotective properties. Among these targets, androgen receptor, estrogen receptor, prostaglandin G/H synthase 2, and inducible nitric oxide synthase play important pathological roles, including the induction of neurogenic inflammation. CQ granules may have therapeutic effectiveness for numerous diseases in addition to respiratory diseases, including neoplasms, digestive system diseases, cardiovascular diseases, respiratory tract diseases and nervous system diseases. In vivo, CQ granules are effective in treating pulmonary inflammation and downregulate neuropeptides in the bronchoalveolar lavage fluid after PM2.5 exposure. CQ granules significantly decreased the levels of neurokinin A, neurokinin B and calcitonin gene-related peptide in the lung and dorsal root ganglia. CQ also significantly suppressed the upregulation of p-extracellular regulated protein kinase 1/2 and p-methyl ethyl ketone 1/2 induced by PM2.5 exposure. CONCLUSION: CQ granules have potential for the treatment of neurogenic inflammation induced by PM2.5 in vivo, and the mechanism might involve downregulation of neuropeptides in the BALF, lung and dorsal root ganglia.
Asunto(s)
Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/química , Inflamación Neurogénica/tratamiento farmacológico , Material Particulado/toxicidad , Animales , Humanos , Masculino , Inflamación Neurogénica/etiología , Inflamación Neurogénica/genética , Inflamación Neurogénica/metabolismo , Neuropéptidos/genética , Neuropéptidos/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Neumonía/tratamiento farmacológico , Neumonía/genética , Neumonía/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Despite the great search for an effective approach to minimize secondary injury in spinal cord injury (SCI) setting, there have been limited advances. Roflumilast is a selective inhibitor of phosphodiesterase 4 with potent anti-inflammatory properties. Here, we sought to explore Roflumilast efficacy in the improvement of locomotor and sensory deficits of SCI. In an animal setting, 50 male rats were randomly assigned to five groups: an SCI group receiving Placebo, three SCI groups receiving Roflumilast at the doses of 0.25, 0.5, and 1 mg/kg prior to T9 vertebra laminectomy, and a sham-operated group. Locomotor, mechanical, and thermal activities were evaluated for 28 days. At the end of the study, spinal cord samples were taken to assess the relative ratio of microglial subtypes, including M1 and M2, histopathological changes, levels of pro-inflammatory (TNF-α and IL-1ß) and anti-inflammatory (IL-10) biomarkers, and cAMP level. Repeated measure analysis revealed significant effect for time-treatment interaction on locomotion [F (24, 270) = 280.7, p < 0.001], thermal sensitivity [F (16, 180) = 4.35, p < 0.001], and mechanical sensitivity [F (16, 180) = 7.96, p < 0.001]. As expected, Roflumilast significantly increased the expression of spinal cAMP. H&E staining exhibited lesser histopathological disruptions in Roflumilast-treated rodents. We also observed a significant reduction in the M1/M2 ratio (p values < 0.001) as well as in pro-inflammatory biomarkers following the administration of Roflumilast to the injured rats. Furthermore, IL-10 level was increased in rodents receiving 1 mg/kg of the reagent. In conclusion, the increased spinal cAMP following Roflumilast therapy might attenuate neuroinflammation via altering microglial activity; therefore, it could be considered as an alternative therapeutic agent for SCI complications.
Asunto(s)
Agnosia/metabolismo , Aminopiridinas/uso terapéutico , Benzamidas/uso terapéutico , Microglía/metabolismo , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Traumatismos de la Médula Espinal/metabolismo , Médula Espinal/metabolismo , Tabes Dorsal/metabolismo , Agnosia/etiología , Agnosia/prevención & control , Animales , AMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Ciclopropanos/uso terapéutico , Modelos Animales de Enfermedad , Humanos , Masculino , Microglía/patología , Inflamación Neurogénica , Ratas , Médula Espinal/patología , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/tratamiento farmacológico , Tabes Dorsal/etiología , Tabes Dorsal/prevención & controlRESUMEN
The hypothalamus is a crucial organ for the maintenance of appropriate body fat storage. Neurons in the hypothalamic arcuate nucleus (ARH) detect energy shortage or surplus via the circulating concentrations of metabolic hormones and nutrients, and then coordinate energy intake and expenditure to maintain energy homeostasis. Malfunction or loss of hypothalamic ARH neurons results in obesity. Accumulated evidence suggests that hypothalamic inflammation is a key pathological mechanism that links chronic overconsumption of a high-fat diet (HFD) with the development of obesity and related metabolic complications. Interestingly, overnutrition-induced hypothalamic inflammation occurs specifically in the ARH, where microglia initiate an inflammatory response by releasing proinflammatory cytokines and chemokines in response to excessive fatty acid flux. Upon more prolonged HFD consumption, astrocytes and perivascular macrophages become involved and sustain hypothalamic inflammation. ARH neurons are victims of hypothalamic inflammation, but they may actively participate in hypothalamic inflammation by sending quiescence or stress signals to surrounding glia. In this mini-review, we describe the current state of knowledge regarding the contributions of neurons and glia, and their interactions, to HFD-induced hypothalamic inflammation.
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Tejido Adiposo/inmunología , Hipotálamo/inmunología , Inflamación/metabolismo , Macrófagos/inmunología , Microglía/inmunología , Neuronas/inmunología , Obesidad/inmunología , Animales , Citocinas/metabolismo , Dieta Alta en Grasa , Metabolismo Energético , Humanos , Inmunidad Celular , Inflamación NeurogénicaRESUMEN
Alzheimer's disease (AD) includes several hallmarks comprised of amyloid-ß (Aß) deposition, tau neuropathology, inflammation, and memory impairment. Brain metabolism becomes uncoupled due to aging and other AD risk factors, which ultimately lead to impaired protein clearance and aggregation. Increasing evidence indicates a role of arginine metabolism in AD, where arginases are key enzymes in neurons and glia capable of depleting arginine and producing ornithine and polyamines. However, currently, it remains unknown if the reduction of arginase 1 (Arg1) in myeloid cell impacts amyloidosis. Herein, we produced haploinsufficiency of Arg1 by the hemizygous deletion in myeloid cells using Arg1fl/fl and LysMcreTg/+ mice crossed with APP Tg2576 mice. Our data indicated that Arg1 haploinsufficiency promoted Aß deposition, exacerbated some behavioral impairment, and decreased components of Ragulator-Rag complex involved in mechanistic target of rapamycin complex 1 (mTORC1) signaling and autophagy. Additionally, Arg1 repression and arginine supplementation both impaired microglial phagocytosis in vitro. These data suggest that proper function of Arg1 and arginine metabolism in myeloid cells remains essential to restrict amyloidosis.
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Péptidos beta-Amiloides/metabolismo , Amiloidosis/metabolismo , Arginasa/metabolismo , Déficit de la Atención y Trastornos de Conducta Disruptiva/metabolismo , Células Mieloides/fisiología , Animales , Arginasa/genética , Autofagia , Conducta Animal , Modelos Animales de Enfermedad , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones , Ratones Transgénicos , Inflamación Neurogénica , Transducción de SeñalRESUMEN
TRPA1 is a cation channel located on the plasma membrane of many types of human and animal cells, including skin sensory neurons and epithelial cells of the intestine, lungs, urinary bladder, etc. TRPA1 is the major chemosensor that also responds to thermal and mechanical stimuli. Substances that activate TRPA1, e.g., allyl isothiocyanates (pungent components of mustard, horseradish, and wasabi), cinnamaldehyde from cinnamon, organosulfur compounds from garlic and onion, tear gas, acrolein and crotonaldehyde from cigarette smoke, etc., cause burning, mechanical and thermal hypersensitivity, cough, eye irritation, sneezing, mucus secretion, and neurogenic inflammation. An increased activity of TRPA1 leads to the emergence of chronic pruritus and allergic dermatitis and is associated with episodic pain syndrome, a hereditary disease characterized by episodes of debilitating pain triggered by stress. TRPA1 is now considered as one of the targets for developing new anti-inflammatory and analgesic drugs. This review summarizes information on the structure, function, and physiological role of this channel, as well as describes known TRPA1 ligands and their significance as therapeutic agents in the treatment of inflammation-associated pain.
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Analgésicos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Inflamación Neurogénica/tratamiento farmacológico , Dolor/tratamiento farmacológico , Canal Catiónico TRPA1/antagonistas & inhibidores , Analgésicos/química , Animales , Antiinflamatorios no Esteroideos/química , Humanos , Ligandos , Estructura Molecular , Inflamación Neurogénica/metabolismo , Dolor/metabolismo , Canal Catiónico TRPA1/química , Canal Catiónico TRPA1/metabolismoRESUMEN
Oxymatrine (OMT), isolated from Sophora flavescens or Sophora alopecuroides, possesses various pharmacological and biological activities, including anti-inflammatory, anti-oxidant, and anti-diabetic properties. Microglia cells, the resident immune cells in the central nervous system (CNS), play a key role in neurodegenerative diseases. In this study, the neuroinflammatory effects of OMT and its mechanisms were investigated by Aß1-42-induced rat brain tissue model and primary microglia cells model. The hematoxylin-eosin (HE) staining and immunohistochemistry results showed that OMT could reduce neuronal damage and inhibit microglia activation in the model tissue. The in vitro experiments revealed that OMT could decrease the levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and nitric oxide (NO), and down-regulate the expression of iNOS and COX-2 in a dose-dependent manner. Furthermore, OMT inhibited phosphorylation of JNK, ERK 1/2, P-p38 and NF-κB in Aß1-42-induced microglia cells. In summary, OMT exhibits anti-neuroinflammatory effects and the anti-inflammatory activity of OMT is related to the regulation of MAPK and NF-κB signaling pathways.
Asunto(s)
Alcaloides/metabolismo , Péptidos beta-Amiloides/inmunología , Microglía/metabolismo , Enfermedades Neurodegenerativas/inmunología , Inflamación Neurogénica/inmunología , Fragmentos de Péptidos/inmunología , Quinolizinas/metabolismo , Animales , Células Cultivadas , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas , Medicina Tradicional China , Microglía/patología , FN-kappa B/metabolismo , Ratas , Ratas Sprague-Dawley , Sophora/inmunologíaRESUMEN
BACKGROUND: The elucidation of the biological roles of individual active compounds in terms of their in vivo bio-distribution and bioactivity could provide crucial information to understand how natural compounds work together as treatments for diseases. PURPOSE: We examined the functional roles of Byakangelicin (Byn) to improve the brain accumulation of active compounds, e.g., umbelliferone (Umb), curcumin (Cur), and doxorubicin (Dox), and consequently to enhance their biological activities. METHODS: Active compounds were administered intravenously to mice, with or without Byn, after which organs were isolated and visualized for their ex vivo fluorescence imaging to determine the bio-distribution of each active compound in vivo. For the in vivo bioactivity, Cur, either with or without Byn, was administered to a lipopolysaccharide (LPS)-induced neuro-inflammation model for 5 days, and its anti-inflammatory effects were examined by ELISA using a brain homogenate and serum. RESULTS: We successfully demonstrated that the levels of active compounds (Umb, Cur, and Dox) in the brain, lung, and pancreas were greatly elevated by the addition of Byn via direct ex vivo fluorescence monitoring. In addition, sufficient accumulation of the active compound, Cur, greatly reduced LPS-induced neuro-inflammation in vivo. CONCLUSION: Byn could serve as a modulator to allow improved brain accumulation of diverse active compounds (Umb, Cur, and Dox) and enhanced therapeutic effects.
Asunto(s)
Curcumina/metabolismo , Doxorrubicina/metabolismo , Furocumarinas/farmacocinética , Inflamación Neurogénica/tratamiento farmacológico , Umbeliferonas/metabolismo , Administración Intravenosa , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Curcumina/química , Modelos Animales de Enfermedad , Doxorrubicina/sangre , Doxorrubicina/química , Femenino , Furocumarinas/administración & dosificación , Humanos , Lipopolisacáridos/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Umbeliferonas/sangre , Umbeliferonas/químicaRESUMEN
It is well-established that bacterial lipopolysaccharides (LPS) can promote neuroinflammation through receptor Toll-like 4 activation and induces sickness behavior in mice. This phenomenon triggers changes in membranes lipid dynamics to promote the intracellular cell signaling. Desorption electrospray ionization mass spectrometry (DESI-MS) is a powerful technique that can be used to image the distribution of lipids in the brain tissue directly. In this work, we characterize the LPS-induced neuroinflammation and the lipid dynamics in C57BL/6 mice at 3 and 24â¯h after LPS injection. We have observed that intraperitoneal administration of LPS (5â¯mg/kg body weight) induces sickness behavior and triggers a peripheral and cerebral increase of pro- and anti-inflammatory cytokine levels after 3â¯h, but only IL-10 was upregulated after 24â¯h. Morphological analysis of hypothalamus, cortex and hippocampus demonstrated that microglial activation was present after 24â¯h of LPS injection, but not at 3â¯h. DESI-MS revealed a total of 14 lipids significantly altered after 3 and 24â¯h and as well as their neuroanatomical distribution. Multivariate statistical analyzes have shown that ions associated with phosphatidylethanolamine [PE(38:4)] and docosatetraenoic acid [FA (22:4)] could be used as biomarkers to distinguish samples from the control or LPS treated groups. Finally, our data demonstrated that monitoring cerebral lipids dynamics and its neuroanatomical distribution can be helpful to understand sickness behavior and microglial activation after LPS administration.
Asunto(s)
Lípidos/inmunología , Inflamación Neurogénica/inmunología , Neuroinmunomodulación/inmunología , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/metabolismo , Citocinas/metabolismo , Hipocampo/diagnóstico por imagen , Hipocampo/metabolismo , Hipotálamo/diagnóstico por imagen , Hipotálamo/metabolismo , Conducta de Enfermedad/fisiología , Lipopolisacáridos/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/inmunología , Transducción de Señal , Espectrometría de Masa por Ionización de Electrospray/métodosRESUMEN
Isoalantolactone (ISO) is a sesquiterpene lactone isolated from Inula helenium that has been known to exhibit anti-inflammatory effect. Nevertheless, the effects of ISO on neuroinflammation have not been explored. BV2 microglia cells were pretreated with ISO and then stimulated with LPS. ISO attenuated the production of inflammatory mediators, such as TNF-α, IL-1ß, NO, and PGE2 in LPS-stimulated BV2 microglia cells. ISO suppressed the LPS-induced NF-κB activation in a concentration-dependent manner. The expression of Nrf2 and HO-1 were increased by the treatment of ISO. Inhibition of Nrf2 by siRNA could reverse the anti-inflammatory effects of ISO, as confirmed by the reversed inflammatory mediator production. Furthermore, ISO increased the level of phosphorylated GSK-3ß, the upstream molecule of Nrf2. In conclusion, these results indicated that ISO might exhibit its anti-inflammatory effects through activating GSK-3ß-Nrf2 signaling pathway.
Asunto(s)
Antiinflamatorios/uso terapéutico , Microglía/efectos de los fármacos , Inflamación Neurogénica/tratamiento farmacológico , Sesquiterpenos/uso terapéutico , Animales , Línea Celular , Dinoprostona/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Interleucina-1beta/metabolismo , Inula/inmunología , Lipopolisacáridos/inmunología , Ratones , Microglía/fisiología , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Fosforilación , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
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.
Asunto(s)
Antirretrovirales/efectos adversos , Corazón/efectos de los fármacos , Magnesio/uso terapéutico , Inflamación Neurogénica/inducido químicamente , Inflamación Neurogénica/prevención & control , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/uso terapéutico , Animales , Terapia Antirretroviral Altamente Activa/efectos adversos , Cardiotoxinas/efectos adversos , Expresión Génica , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , VIH-1/genética , Corazón/fisiopatología , Riñón/efectos de los fármacos , Riñón/fisiopatología , Masculino , Inflamación Neurogénica/fisiopatología , Activación Neutrófila/efectos de los fármacos , Estrés Nitrosativo/efectos de los fármacos , Ratas Endogámicas F344 , Ratas TransgénicasRESUMEN
Brain inflammation is associated with cognitive dysfunction, especially in elderly. Trigonelline is a plant alkaloid and a major component of coffee and fenugreek with anti-diabetic, antioxidant, anti-inflammatory, and neuroprotective effects. In this study, the beneficial effect of trigonelline against lipopolysaccharide (LPS)-induced cognitive decline was assessed in the rat. LPS was injected i.p. at a dose of 500⯵g/kg to induce neuroinflammation and trigonelline was administered p.o. at doses of 20, 40, or 80â¯mg/kg/day 1â¯h after LPS that continued for one week. Trigonelline-treated LPS-challenged rats showed improved spatial recognition memory in Y maze, discrimination ratio in novel object discrimination test, and retention and recall in passive avoidance paradigm. Additionally, trigonelline lowered hippocampal malondialdehyde (MDA) and acetylcholinesterase (AChE) activity and improved superoxide dismutase (SOD), catalase, and glutathione (GSH). Furthermore, trigonelline depressed hippocampal nuclear factor-kappaB (NF-κB), toll-like receptor 4 (TLR4), and tumor necrosis factor α (TNF α) in LPS-challenged rats. All of the effects of trigonelline followed a dose-dependent pattern and in some aspects, it acted even better than the routinely-used anti-inflammatory drug dexamethasone. Collectively, trigonelline is capable to diminish LPS-induced cognitive decline via suppression of hippocampal oxidative stress and inflammation and appropriate modulation of NF-κB/TLR4 and AChE activity.
Asunto(s)
Alcaloides/uso terapéutico , Antioxidantes/uso terapéutico , Encéfalo/efectos de los fármacos , Discapacidades para el Aprendizaje/tratamiento farmacológico , Trastornos de la Memoria/tratamiento farmacológico , Inflamación Neurogénica/tratamiento farmacológico , Acetilcolinesterasa/metabolismo , Anciano , Animales , Encéfalo/inmunología , Encéfalo/patología , Humanos , Discapacidades para el Aprendizaje/inducido químicamente , Lipopolisacáridos/inmunología , Masculino , Malondialdehído/metabolismo , Trastornos de la Memoria/inducido químicamente , FN-kappa B/metabolismo , Inflamación Neurogénica/inducido químicamente , Estrés Oxidativo/efectos de los fármacos , Reconocimiento Visual de Modelos/efectos de los fármacos , Ratas , Ratas Wistar , Transducción de Señal , Receptor Toll-Like 4/metabolismoRESUMEN
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.