RESUMEN
Neonatal immune activation (NIA) through exposure to lipopolysaccharide (LPS) induces adult behavioral changes in rodents that resemble symptoms of developmental disorders, such as autism spectrum disorder. The neonatal timing of LPS exposure appears to play a crucial role in determining the nature and extent of long-term changes. This study aims to explore whether a 3-day LPS-NIA triggers sex- and age-related changes in gut function, potentially linking LPS-NIA to gastrointestinal dysfunction. Male and female Swiss mice received intraperitoneal injections of LPS or saline on postnatal days (PN) 3, 5, and 7. At PN35 (juvenile) and PN70 (adult), gut inflammation and oxidative stress were evaluated in addition to assessments of working memory, depressive-like symptoms, sociability, and repetitive behavior. Gut examination showed elevated C-X-C motif chemokine receptor 3 (CXCR3) in LPS-NIA mice, while MyD88 and Zonulin expressions were significantly higher only in adult LPS-NIA females. Interleukin (IL)-23 expression increased in juvenile and adult male and juvenile female LPS-NIA mice. Oxidative changes included decreased duodenal reduced glutathione (GSH) in juvenile females and ileal GSH in adult females exposed to LPS-NIA. Regarding behavioral alterations, adult LPS-NIA females exhibited depressive-like behavior. Working memory deficits were observed across all LPS-NIA groups. Only juvenile LPS-NIA females increased grooming, while rearing was higher in adult LPS-NIA mice of both sexes. The findings imply that LPS-NIA impacts intestinal barrier function and causes gut inflammatory alterations that are sex- and age-specific. These findings pave the way for exploring potential mechanisms that could contribute to LPS-induced gastrointestinal disturbances among individuals with ASD.
Asunto(s)
Animales Recién Nacidos , Lipopolisacáridos , Caracteres Sexuales , Animales , Lipopolisacáridos/toxicidad , Femenino , Ratones , Masculino , Factores de Edad , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Envejecimiento/inmunología , Envejecimiento/fisiologíaRESUMEN
Açaí seed extract (ASE) is obtained from Euterpe oleracea Mart. (açaí) plant (Amazon region) has high nutritional and functional value. ASE is rich in polyphenolic compounds, mainly proanthocyanidins. Proanthocyanidins can modulate the immune system and oxidative stress by inhibiting the toll-like receptor-4 (TLR-4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor-κB (NF-κB) pathway. A great deal of evidence suggests that inflammatory cytokines and oxidative stress contribute to the pathogenesis of intestinal mucositis, and these events can lead to intestinal dysmotility. We hypothesized that ASE acts as an anti-inflammatory and antioxidant compound in intestinal mucositis induced by 5-fluorouracil (5-FU) through modulation of the TLR-4/MyD88/phosphatidylinositol-3-kinase α/mechanistic target of rapamycin/NF-κBp65 pathway. The animals were divided into linear 5-FU (450 mg/kg) and 5-FU + ASE (10, 30, and 100 mg/kg) groups. The weight loss of the animals was evaluated daily. Samples from duodenum, jejunum, and ileum were obtained for histopathological, biochemical, and functional analyses. ASE reduced weight loss, inflammatory parameters (interleukin-1ß; tumor necrosis factor-α; myeloperoxidase activity) and the gene expression of mediators involved in the TLR-2/MyD88/NF-κB pathway. ASE prevented histopathological changes with beneficial effects on gastrointestinal transit delay, gastric emptying, and intestinal absorption/permeability. In conclusion, ASE protects the integrity of the intestinal epithelial barrier by inhibiting the TLR/MyD88/PI3K/mechanistic target of rapamycin/NF-κBp65 pathway.
Asunto(s)
Euterpe , Fluorouracilo , Mucositis , Factor 88 de Diferenciación Mieloide , Extractos Vegetales , Polifenoles , Semillas , Transducción de Señal , Serina-Treonina Quinasas TOR , Receptor Toll-Like 4 , Animales , Receptor Toll-Like 4/metabolismo , Mucositis/inducido químicamente , Mucositis/tratamiento farmacológico , Mucositis/prevención & control , Mucositis/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Transducción de Señal/efectos de los fármacos , Extractos Vegetales/farmacología , Semillas/química , Polifenoles/farmacología , Masculino , Euterpe/química , Ratones , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Factor de Transcripción ReIA/metabolismo , Antioxidantes/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Antiinflamatorios/farmacología , FN-kappa B/metabolismoRESUMEN
Mania is associated with disturbed dopaminergic transmission in frontotemporal regions. D-amphetamine (AMPH) causes increased extracellular DA levels, considered an acknowledged mania model in rodents. Doxycycline (DOXY) is a second-generation tetracycline with promising neuroprotective properties. Here, we tested the hypothesis that DOXY alone or combined with Lithium (Li) could reverse AMPH-induced mania-like behavioral alterations in mice by the modulation of monoamine levels in brain areas related to mood regulation, as well as cytoprotective and antioxidant effects in hippocampal neurons. Male Swiss mice received AMPH or saline intraperitoneal (IP) injections for 14 days. Between days 8-14, mice receive further IP doses of DOXY, Li, or their combination. For in vitro studies, we exposed hippocampal neurons to DOXY in the presence or absence of AMPH. DOXY alone or combined with Li reversed AMPH-induced risk-taking behavior and hyperlocomotion. DOXY also reversed AMPH-induced hippocampal and striatal hyperdopaminergia. In AMPH-exposed hippocampal neurons, DOXY alone and combined with Li presented cytoprotective and antioxidant effects, while DOXY+Li also increased the expression of phospho-Ser133-CREB. Our results add novel evidence for DOXY's ability to reverse mania-like features while revealing that antidopaminergic activity in some brain areas, such as the hippocampus and striatum, as well as hippocampal cytoprotective effects may account for this drug's antimanic action. This study provides additional rationale for designing clinical trials investigating its potential as a mood stabilizer agent.
Asunto(s)
Antioxidantes , Doxiciclina , Hipocampo , Manía , Neuronas , Animales , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ratones , Antioxidantes/farmacología , Manía/inducido químicamente , Manía/tratamiento farmacológico , Doxiciclina/farmacología , Conducta Animal/efectos de los fármacos , Células Cultivadas , Anfetamina/farmacología , Anfetamina/toxicidad , Modelos Animales de Enfermedad , Estimulantes del Sistema Nervioso Central/toxicidad , Monoaminas Biogénicas/metabolismo , Dextroanfetamina/farmacología , Dextroanfetamina/toxicidad , Antimaníacos/farmacología , Fármacos Neuroprotectores/farmacologíaRESUMEN
AIM: The aim of the present study was to investigate the anti-inflammatory response mediated of the M1 muscarinic acetylcholine receptor (mAChR) during experimental colitis. MATERIAL AND METHODS: After the induction of 6% acetic acid colitis, mice were treated with McN-A-343 0.5, 1.0, and 1.5 mg/kg or dexamethasone (DEXA, 2.0 mg/kg) or pirenzepine (PIR, 10 mg/kg; M1 mAChR antagonist). Colonic inflammation was assessed by macroscopic and microscopic lesion scores, colonic wet weight, myeloperoxidase (MPO) activity, interleukin-1 beta (IL1-ß) levels and tumor necrosis factor alpha (TNF-α), glutathione (GSH), malondialdehyde (MDA) and nitrate and nitrite (NO3/NO2), mRNA expression of IKKα, nuclear factor kappa beta (NF-kB) and cyclooxygenase-2 (COX-2), as well protein expression of NF-kB and COX-2. RESULTS: Treatment with McN-A-343 at a concentration of 1.5 mg/kg showed a significant reduction in intestinal damage as well as a decrease in wet weight, MPO activity, pro-inflammatory cytokine concentration, markers of oxidative stress and expression of inflammatory mediators. The action of the M1 agonist by the administration of pirenzepine, which promoted the blocking of the mAChR M1-mediated anti-inflammatory response, has also been proven. CONCLUSION: The results suggest that peripheral colonic M1 mAChR is involved in reversing the pro-inflammatory effect of experimentally induced colitis, which may represent a promising therapeutic alternative for patients with ulcerative colitis.
Asunto(s)
Cloruro de (4-(m-Clorofenilcarbamoiloxi)-2-butinil)trimetilamonio/farmacología , Colitis Ulcerosa/tratamiento farmacológico , Cloruro de (4-(m-Clorofenilcarbamoiloxi)-2-butinil)trimetilamonio/metabolismo , Animales , Colitis/tratamiento farmacológico , Colitis/metabolismo , Colitis Ulcerosa/metabolismo , Colon/metabolismo , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Dexametasona/farmacología , Modelos Animales de Enfermedad , Glutatión/metabolismo , Inflamación/patología , Mediadores de Inflamación/metabolismo , Interleucina-1beta/metabolismo , Masculino , Malondialdehído/metabolismo , Ratones , Agonistas Muscarínicos/farmacología , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Receptor Muscarínico M1 , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Euterpe oleracea Mart., commonly known as açaí, has been demonstrated to exhibit significantly antioxidant and inflammatory activities in experimental models. These effects of the hydroalcoholic extract from the açaí seed (ASE) were investigated in TNBS-induced (2,4,6-trinitrobenzenesulfonic acid) acute colitis model in rats. Wistar rats (180-220 g) were orally pretreated with saline (0.3 mL), ASE (10, 30 and 100 mg/kg) and dexamethasone (control group, 1 mg/kg) once daily for 3 days starting before TNBS instillation. On day 3 after TNBS, the animals were euthanized, the portion of distal colon was collected and washed with 0.9% saline for macroscopy and histological evaluation, glutathione (GSH) and malonyldialdehyde (MDA) levels, myeloperoxidase (MPO) and catalase (CAT) activity, nitrate and nitrite (NO3/NO2) concentration, pro-inflammatory cytokines levels and intestinal barrier integrity. We also evaluated Toll-like Receptor 4/cyclooxygenase-2/nuclear factor kappa B expression as a possible mechanism related to the ASE effects. Treatment with ASE 100 mg/kg decreased significantly macroscopic and microscopic damage induced by TNBS. In addition, MPO activity, TNF-α (tumor necrosis factor-alpha) and IL-1ß (interleukin 1) levels were reduced in rats with colitis. ASE 100 mg/kg restored GSH and MDA levels, CAT activity, NO3/NO2 concentration and improved the intestinal barrier integrity in the TNBS group. ASE 100 mg/kg significantly reduced TNBS-induced expression of the TLR4, COX-2 and NF-κB p65. ASE 100 mg/kg improved macroscopy and histological parameters, inflammation, intestinal barrier integrity and nitric and oxidative stress through the TLR-4/COX-2/NF-κB pathway.
Asunto(s)
Colitis/tratamiento farmacológico , Euterpe/química , Inflamación/tratamiento farmacológico , Extractos Vegetales/farmacología , Animales , Antioxidantes/administración & dosificación , Antioxidantes/aislamiento & purificación , Antioxidantes/farmacología , Colitis/fisiopatología , Ciclooxigenasa 2/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inflamación/fisiopatología , Masculino , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/administración & dosificación , Ratas , Ratas Wistar , Receptor Toll-Like 4/metabolismo , Ácido TrinitrobencenosulfónicoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: There are many reports of pharmacological activities of extracts and fractions of different vegetable-derived products in the scientific literature and in folk medicine. Ethnopharmacological use of these products by various communities continues to be extensively explored, and they account for more than half of all medications used worldwide. Polysaccharides (PLS) extracted from plants such as Morinda Citrifolia Linn present therapeutic potential in treatment of inflammatory bowel diseases (IBD) such as ulcerative colitis (UC). AIM OF THE STUDY: To evaluate the anti-inflammatory action of Noni-PLS against the intestinal damage in UC induced by acetic acid in mice. MATERIALS AND METHODS: In acetic acid-induced colitis, the mice were treated intraperitoneally (ip) with Noni-PLS (0.1, 0.3, and 3.0â¯mg/kg) or subcutaneously (sc) with dexamethasone (2.0â¯mg/kg) 30â¯min before euthanasia to determine the best dose of Noni-PLS with an anti-inflammatory effect in the course of UC. The colonic tissue samples were collected for macroscopic, wet weight, microscopic and biochemical (myeloperoxidase (MPO), glutathione (GSH), malondialdehyde (MDA), nitrate/nitrite (NO3/NO2), cytokines, cyclooxygenase (COX-2) and inducible nitric oxide (iNOS)) analyses. RESULTS: Treatment with Noni-PLS reduced the intestinal damage induced by acetic acid as it reduced macroscopic and microscopic scores and the wet weight of the colon. In addition, MPO activity and levels of GSH, MDA, NO3/NO2, pro-inflammatory cytokines, and COX-2 expression reduced. CONCLUSIONS: This study suggests that Noni-PLS exhibits anti-inflammatory action against intestinal damage by reducing inflammatory cell infiltration, oxidative stress, pro-inflammatory action of cytokines, COX-2 and iNOS expression in the inflamed colon. Noni-PLS shows therapeutic potential against inflammatory disorders like UC.
Asunto(s)
Antiinflamatorios/uso terapéutico , Colitis/tratamiento farmacológico , Morinda , Polisacáridos/uso terapéutico , Ácido Acético , Animales , Antiinflamatorios/farmacología , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/patología , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Ciclooxigenasa 2/metabolismo , Frutas , Glutatión/metabolismo , Interleucina-1beta/metabolismo , Masculino , Malondialdehído/metabolismo , Ratones , Nitratos/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Nitritos/metabolismo , Peroxidasa/metabolismo , Polisacáridos/farmacología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The N-acylhydrazone (NAH) moiety is considered a privileged structure, being present in many compounds with diverse pharmacological activities. Among the activities attributed to NAH derivatives anti-inflammatory and analgesic ones are recurrent. As part of a research program aiming at the design of new analgesic and anti-inflammatory lead-candidates, a series of cyclohexyl-N-acylhydrazones 10-26 were structurally designed from molecular modification on the prototype LASSBio-294, representing a new class of cycloalkyl analogues. Compounds 10-26 and their conformationally restricted analogue 9 were synthetized and evaluated as analgesic and anti-inflammatory agents in classical pharmacologic protocols. The cyclohexyl-N-acylhydrazones 10-26 and the cyclohexenyl analogue 9 showed great anti-inflammatory and/or analgesic activities, but compound 13 stood out as a new prototype to treat acute and chronic painful states due to its important analgesic activity in a neuropathic pain model.