Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 42
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
Neurogastroenterol Motil ; : e14020, 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33112027

RESUMO

BACKGROUND: Cisplatin is an antineoplastic drug known to produce intense vomiting, gastric dysmotility, and peripheral neuropathy. Monosodium glutamate (MSG) is a flavor enhancer with prokinetic properties potentially useful for cancer patients under chemotherapy. Our aim was to test whether MSG may improve gastrointestinal motor dysfunction and other adverse effects induced by repeated cisplatin in rats. METHODS: Male Wistar rats were exposed or not to MSG (4 g L-1 ) in drinking water from week 0 to 1 week after treatment. On the first day of weeks 1-5, rats were treated with saline or cisplatin (2 mg kg-1  week-1 , ip). Gastrointestinal motility was measured by radiological methods after first and fifth administrations, as well as 1 week after treatment finalization. One week after treatment, the threshold for mechanical somatic sensitivity was recorded. Finally, samples of stomach, terminal ileum and kidneys were evaluated in sections using conventional histology. The myenteric plexus was immunohistochemically evaluated on distal colon whole-mount preparations. KEY RESULTS: Monosodium glutamate prevented the development of cisplatin-induced neuropathy and partially improved intestinal transit after the fifth cisplatin administration with little impact on gastric dysmotility. MSG did not improve the histological damage of gut wall, but prevented the changes induced by cisplatin in the colonic myenteric plexus. CONCLUSION AND INFERENCES: Our results suggest that MSG can improve some dysfunctions caused by anticancer chemotherapy in the gut and other systems, associated, at least partially, with neuroprotectant effects. The potentially useful adjuvant role of this food additive to reduce chemotherapy-induced sequelae warrants further evaluation.

2.
Molecules ; 25(18)2020 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-32962285

RESUMO

Mast cells are key actors in inflammatory reactions. Upon activation, they release histamine, heparin and nerve growth factor, among many other mediators that modulate immune response and neuron sensitization. One important feature of mast cells is that their population is usually increased in animal models and biopsies from patients with irritable bowel syndrome (IBS). Therefore, mast cells and mast cell mediators are regarded as key components in IBS pathophysiology. IBS is a common functional gastrointestinal disorder affecting the quality of life of up to 20% of the population worldwide. It is characterized by abdominal pain and altered bowel habits, with heterogeneous phenotypes ranging from constipation to diarrhea, with a mixed subtype and even an unclassified form. Nutrient intake is one of the triggering factors of IBS. In this respect, certain components of the daily food, such as fatty acids, amino acids or plant-derived substances like flavonoids, have been described to modulate mast cells' activity. In this review, we will focus on the effect of these molecules, either stimulatory or inhibitory, on mast cell degranulation, looking for a nutraceutical capable of decreasing IBS symptoms.

3.
Inflamm Bowel Dis ; 2020 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-32618996

RESUMO

BACKGROUND: Inflammatory bowel disease (IBD) associates with damage to the enteric nervous system (ENS), leading to gastrointestinal (GI) dysfunction. Oxidative stress is important for the pathophysiology of inflammation-induced enteric neuropathy and GI dysfunction. Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a dual functioning protein that is an essential regulator of the cellular response to oxidative stress. In this study, we aimed to determine whether an APE1/Ref-1 redox domain inhibitor, APX3330, alleviates inflammation-induced oxidative stress that leads to enteric neuropathy in the Winnie murine model of spontaneous chronic colitis. METHODS: Winnie mice received APX3330 or vehicle via intraperitoneal injections over 2 weeks and were compared with C57BL/6 controls. In vivo disease activity and GI transit were evaluated. Ex vivo experiments were performed to assess functional parameters of colonic motility, immune cell infiltration, and changes to the ENS. RESULTS: Targeting APE1/Ref-1 redox activity with APX3330 improved disease severity, reduced immune cell infiltration, restored GI function ,and provided neuroprotective effects to the enteric nervous system. Inhibition of APE1/Ref-1 redox signaling leading to reduced mitochondrial superoxide production, oxidative DNA damage, and translocation of high mobility group box 1 protein (HMGB1) was involved in neuroprotective effects of APX3330 in enteric neurons. CONCLUSIONS: This study is the first to investigate inhibition of APE1/Ref-1's redox activity via APX3330 in an animal model of chronic intestinal inflammation. Inhibition of the redox function of APE1/Ref-1 is a novel strategy that might lead to a possible application of APX3330 for the treatment of IBD.

4.
Int J Mol Sci ; 21(9)2020 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-32357565

RESUMO

Cannabis sativa is an aromatic annual flowering plant with several botanical varieties, used for different purposes, like the production of fibers, the production of oil from the seeds, and especially for recreational or medical purposes. Phytocannabinoids (terpenophenolic compounds derived from the plant), include the well-known psychoactive cannabinoid Δ9-tetrahydrocannabinol, and many non-psychoactive cannabinoids, like cannabidiol. The endocannabinoid system (ECS) comprises of endocannabinoid ligands, enzymes for synthesis and degradation of such ligands, and receptors. This system is widely distributed in the gastrointestinal tract, where phytocannabinoids exert potent effects, particularly under pathological (i.e., inflammatory) conditions. Herein, we will first look at the hemp plant as a possible source of new functional food ingredients and nutraceuticals that might be eventually useful to treat or even prevent gastrointestinal conditions. Subsequently, we will briefly describe the ECS and the general pharmacology of phytocannabinoids. Finally, we will revise the available data showing that non-psychoactive phytocannabinoids, particularly cannabidiol, may be useful to treat different disorders and diseases of the gastrointestinal tract. With the increasing interest in the development of functional foods for a healthy life, the non-psychoactive phytocannabinoids are hoped to find a place as nutraceuticals and food ingredients also for a healthy gastrointestinal tract function.

5.
Curr Drug Targets ; 21(14): 1428-1439, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32416686

RESUMO

Ulcerative colitis (UC) and Crohn's disease (CD) are pathological conditions with an unknown aetiology that are characterised by severe inflammation of the intestinal tract and collectively referred to as inflammatory bowel disease (IBD). Current treatments are mostly ineffective due to their limited efficacy or toxicity, necessitating surgical resection of the affected bowel. The management of IBD is hindered by a lack of prognostic markers for clinical inflammatory relapse. Intestinal inflammation associates with the infiltration of immune cells (leukocytes) into, or surrounding the neuronal ganglia of the enteric nervous system (ENS) termed plexitis or ganglionitis. Histological observation of plexitis in unaffected intestinal regions is emerging as a vital predictive marker for IBD relapses. Plexitis associates with alterations to the structure, cellular composition, molecular expression and electrophysiological function of enteric neurons. Moreover, plexitis often occurs before the onset of gross clinical inflammation, which may indicate that plexitis can contribute to the progression of intestinal inflammation. In this review, the bilateral relationships between the ENS and inflammation are discussed. These include the effects and mechanisms of inflammation-induced enteric neuronal loss and plasticity. Additionally, the role of enteric neurons in preventing antigenic/pathogenic insult and immunomodulation is explored. While all current treatments target the inflammatory pathology of IBD, interventions that protect the ENS may offer an alternative avenue for therapeutic intervention.

6.
Behav Pharmacol ; 31(2&3): 136-158, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32168025

RESUMO

The management of pain, particularly chronic pain, is still an area of medical need. In this context, opioids remain a gold standard for the treatment of pain. However, significant side effects, mainly of central origin, limit their clinical use. Here, we review recent progress to improve the therapeutic and safety profiles of opioids for pain management. Characterization of peripheral opioid-mediated pain mechanisms have been a key component of this process. Several studies identified peripheral µ, δ, and κ opioid receptors (MOR, DOR, and KOR, respectively) and nociceptin/orphanin FQ (NOP) receptors as significant players of opioid-mediated antinociception, able to achieve clinically significant effects independently of any central action. Following this, particularly from a medicinal chemistry point of view, main efforts have been directed towards the peripheralization of opioid receptor agonists with the objective of optimizing receptor activity and minimizing central exposure and the associated undesired effects. These activities have allowed the characterization of a great variety of compounds and investigational drugs that show low central nervous system (CNS) penetration (and therefore a reduced side effect profile) yet maintaining the desired opioid-related peripheral antinociceptive activity. These include highly hydrophilic/amphiphilic and massive molecules unable to easily cross lipid membranes, substrates of glycoprotein P (a extrusion pump that avoids CNS penetration), nanocarriers that release the analgesic agent at the site of inflammation and pain, and pH-sensitive opioid agonists that selectively activate at those sites (and represent a new pharmacodynamic paradigm). Hopefully, patients with pain will benefit soon from the incorporation of these new entities.


Assuntos
Analgesia/psicologia , Analgésicos Opioides/farmacologia , Manejo da Dor/métodos , Analgésicos/metabolismo , Analgésicos/farmacologia , Analgésicos Opioides/metabolismo , Animais , Humanos , Dor/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Receptores Opioides/agonistas , Receptores Opioides/metabolismo , Receptores Opioides kappa/agonistas , Receptores Opioides mu/agonistas
7.
Nutrients ; 13(1)2020 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-33383958

RESUMO

Coffee is one of the most popular beverages consumed worldwide. Roasted coffee is a complex mixture of thousands of bioactive compounds, and some of them have numerous potential health-promoting properties that have been extensively studied in the cardiovascular and central nervous systems, with relatively much less attention given to other body systems, such as the gastrointestinal tract and its particular connection with the brain, known as the brain-gut axis. This narrative review provides an overview of the effect of coffee brew; its by-products; and its components on the gastrointestinal mucosa (mainly involved in permeability, secretion, and proliferation), the neural and non-neural components of the gut wall responsible for its motor function, and the brain-gut axis. Despite in vitro, in vivo, and epidemiological studies having shown that coffee may exert multiple effects on the digestive tract, including antioxidant, anti-inflammatory, and antiproliferative effects on the mucosa, and pro-motility effects on the external muscle layers, much is still surprisingly unknown. Further studies are needed to understand the mechanisms of action of certain health-promoting properties of coffee on the gastrointestinal tract and to transfer this knowledge to the industry to develop functional foods to improve the gastrointestinal and brain-gut axis health.


Assuntos
Encéfalo/efeitos dos fármacos , Cafeína/farmacologia , Café/química , Trato Gastrointestinal/efeitos dos fármacos , Anti-Inflamatórios , Antioxidantes/farmacologia , Bebidas , Fibras na Dieta , Microbioma Gastrointestinal , Trato Gastrointestinal/patologia , Humanos , Membrana Mucosa , Polímeros , Polifenóis
8.
Nutrients ; 11(6)2019 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-31234581

RESUMO

The bioaccessibility, metabolism, and excretion of lipids composing spent coffee grounds (SCGs) were investigated. An analysis of mycotoxins and an acute toxicity study in rats were performed for safety evaluation. Total fat, fatty acids, and diterpenes (cafestol and kahweol) were determined in SCGs and their digests obtained in vitro. A pilot repeated intake study was carried out in Wistar rats using a dose of 1 g SCGs/kg b.w. for 28 days. Fat metabolism was evaluated by analysis of total fat, cholesterol, and histology in liver. The dietary fiber effect of SCGs was measured radiographically. The absence of mycotoxins and toxicity was reported in SCGs. A total of 77% of unsaturated fatty acids and low amounts of kahweol (7.09 µg/g) and cafestol (414.39 µg/g) were bioaccessible after in vitro digestion. A significantly lower (p < 0.1) accumulation of lipids in the liver and a higher excretion of these in feces was found in rats treated with SCGs for 28 days. No lipid droplets or liver damage were observed by histology. SCGs acutely accelerated intestinal motility in rats. SCGs might be considered a sustainable, safe, and healthy food ingredient with potential for preventing hepatic steatosis due to their effect as dietary fiber with a high fat-holding capacity.


Assuntos
Coffea/metabolismo , Diterpenos/metabolismo , Ácidos Graxos/metabolismo , Sementes/metabolismo , Animais , Disponibilidade Biológica , Biotransformação , Coffea/toxicidade , Diterpenos/administração & dosagem , Ácidos Graxos/administração & dosagem , Fezes/química , Feminino , Motilidade Gastrointestinal/efeitos dos fármacos , Eliminação Intestinal , Fígado/metabolismo , Masculino , Projetos Piloto , Ratos Wistar , Sementes/toxicidade , Fatores de Tempo
9.
Neurogastroenterol Motil ; 31(8): e13621, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31117152

RESUMO

BACKGROUND: Loperamide is a potent mu opioid receptor agonist available over the counter to treat diarrhea. Although at therapeutic doses loperamide is devoid of central effects, it may exert them if used at high doses or combined with drugs that increase its systemic and/or central bioavailability. Recently, public health and scientific interest on loperamide has increased due to a growing trend of misuse and abuse, and consequent reports on its toxicity. Our aim was to evaluate in the rat the effects of increasing loperamide doses, with increasing likelihood to induce central effects, on gastrointestinal motor function (including gastric dysmotility and nausea-like behavior). METHODS: Male Wistar rats received an intraperitoneal injection of vehicle or loperamide (0.1, 1, or 10 mg kg-1 ). Three sets of experiments were performed to evaluate: (a) central effects (somatic nociceptive thresholds, immobility time, core temperature, spontaneous locomotor activity); (b) general gastrointestinal motility (serial X-rays were taken 0-8 hours after intragastric barium administration and analyzed semiquantitatively, morphometrically, and densitometrically); and (c) bedding intake (a rodent indirect marker of nausea). Animals from sets 1 and 3 were used to evaluate gastric dysmotility ex vivo at 2 and 4 hours after administration, respectively. KEY RESULTS: Loperamide significantly induced antinociception, hypothermia, and hypolocomotion (but not catalepsy) at high doses and dose-dependently reduced gastrointestinal motor function, with the intestine exhibiting higher sensitivity than the stomach. Whereas bedding intake occurred early and transiently, gastric dysmotility was much more persistent. CONCLUSIONS AND INFERENCES: Our results suggest that loperamide-induced nausea and gastric dysmotility might be temporally dissociated.


Assuntos
Antidiarreicos/toxicidade , Motilidade Gastrointestinal/efeitos dos fármacos , Loperamida/toxicidade , Animais , Relação Dose-Resposta a Droga , Hipotermia/induzido quimicamente , Locomoção/efeitos dos fármacos , Loperamida/administração & dosagem , Masculino , Náusea/induzido quimicamente , Nociceptividade/efeitos dos fármacos , Ratos , Ratos Wistar
10.
Front Neurosci ; 13: 449, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31139044

RESUMO

Gastrointestinal (GI) side-effects of chemotherapy present a constant impediment to efficient and tolerable treatment of cancer. GI symptoms often lead to dose reduction, delays and cessation of treatment. Chemotherapy-induced nausea, bloating, vomiting, constipation, and/or diarrhea can persist up to 10 years post-treatment. We have previously reported that long-term 5-fluorouracil (5-FU) administration results in enteric neuronal loss, acute inflammation and intestinal dysfunction. In this study, we investigated whether the cytoprotectant, BGP-15, has a neuroprotective effect during 5-FU treatment. Balb/c mice received tri-weekly intraperitoneal 5-FU (23 mg/kg/d) administration with and without BGP-15 (15 mg/kg/d) for up to 14 days. GI transit was analyzed via in vivo serial X-ray imaging prior to and following 3, 7, and 14 days of treatment. On day 14, colons were collected for assessment of ex vivo colonic motility, neuronal mitochondrial superoxide, and cytochrome c levels as well as immunohistochemical analysis of myenteric neurons. BGP-15 did not inhibit 5-FU-induced neuronal loss, but significantly increased the number and proportion of choline acetyltransferase (ChAT)-immunoreactive (IR) and neuronal nitric oxide synthase (nNOS)-IR neurons in the myenteric plexus. BGP-15 co-administration significantly increased mitochondrial superoxide production, mitochondrial depolarization and cytochrome c release in myenteric plexus and exacerbated 5-FU-induced colonic inflammation. BGP-15 exacerbated 5-FU-induced colonic dysmotility by reducing the number and proportion of colonic migrating motor complexes and increasing the number and proportion of fragmented contractions and increased fecal water content indicative of diarrhea. Taken together, BGP-15 co-treatment aggravates 5-FU-induced GI side-effects, in contrast with our previous findings that BGP-15 alleviates GI side-effects of oxaliplatin.

11.
Neurogastroenterol Motil ; 31(9): e13651, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31145538

RESUMO

BACKGROUND: Food and diet are central issues for proper functioning of the cardiovascular (CV) system and gastrointestinal (GI) tract. We hypothesize that different types of dietary FAs affect CV parameters as well as GI motor function and visceral sensitivity. METHODS: Male Wistar rats were fed with control diet (CTRL), diet supplemented with 7% soybean oil (SOY), SOY + 3.5% virgin coconut oil (COCO), and SOY + 3.5% evening primrose oil (EP) for 4 weeks. The content of insoluble fiber in CTRL was higher than in SOY, COCO, or EP. Body weight gain and food/water intake were measured. At day 28, biometric, biochemical, CV parameters, GI motor function (X-ray and colon bead expulsion test), and visceral sensitivity were evaluated. Changes in propulsive colonic activity were determined in vitro. The colon and adipose tissue were histologically studied; the number of mast cells (MCs) in the colon was calculated. RESULTS: SOY, COCO, and EP had increased body weight gain but decreased food intake vs CTRL. Water consumption, biometric, biochemical, and CV parameters were comparable between groups. SOY increased the sensitivity to colonic distention. All groups maintained regular propulsive neurogenic contractions; EP delayed colonic motility (P < 0.01). SOY, COCO, and EP displayed decreased size of the cecum, lower number and size of fecal pellets, and higher infiltration of MCs to the colon (P < 0.001). CONCLUSIONS AND INFERENCES: Dietary FAs supplementation and lower intake of insoluble fiber can induce changes in the motility of the lower GI tract, in vivo and in vitro, but CV function and visceral sensitivity are not generally affected.


Assuntos
Pressão Sanguínea/fisiologia , Fibras na Dieta/administração & dosagem , Ácidos Graxos/administração & dosagem , Motilidade Gastrointestinal/fisiologia , Frequência Cardíaca/fisiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Óleo de Coco/administração & dosagem , Motilidade Gastrointestinal/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Óleo de Soja/administração & dosagem
12.
J Neurogastroenterol Motil ; 25(2): 300-315, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-30870877

RESUMO

Background/Aims: Gastrointestinal adverse effects have a major impact on health and quality of life in analgesics users. Non-invasive methods to study gastrointestinal motility are of high interest. Fluoroscopy has been previously used to study gastrointestinal motility in small experimental animals, but they were generally anesthetized and anesthesia itself may alter motility. In this study, our aim is to determine, in conscious rats, the effect of increasing doses of 2 opioid (morphine and loperamide) and 1 cannabinoid (WIN 55,212-2) agonists on colonic motility using fluoroscopic recordings and spatio-temporal maps. Methods: Male Wistar rats received barium sulfate intragastrically, 20-22 hours before fluoroscopy, so that stained fecal pellets could be seen at the time of recording. Animals received an intraperitoneal administration of morphine, loperamide, or WIN 55,212-2 (at 0.1, 1, 5, or 10 mg/kg) or their corresponding vehicles (saline, Cremophor, and Tocrisolve, respectively), 30 minutes before fluoroscopy. Rats were conscious and placed within movement-restrainers for the length of fluoroscopic recordings (120 seconds). Spatio-temporal maps were built, and different parameters were analyzed from the fluoroscopic recordings in a blinded fashion to evaluate colonic propulsion of endogenous fecal pellets. Results: The analgesic drugs inhibited propulsion of endogenous fecal pellets in a dose-dependent manner. Conclusions: Fluoroscopy allows studying colonic propulsion of endogenous fecal pellets in conscious rats. Our method may be applied to the non-invasive study of the effect of different drug treatments and pathologies.

13.
Foods ; 8(2)2019 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-30759878

RESUMO

Melanoidins present in coffee silverskin, the only by-product of the roasting process, are formed via the Maillard reaction. The exact structure, biological properties, and mechanism of action of coffee silverskin melanoidins, remain unknown. This research work aimed to contribute to this novel knowledge. To achieve this goal, melanoidins were obtained from an aqueous extract of Arabica coffee silverskin (WO2013004873A1) and was isolated through ultrafiltration (>10 kDa). The isolation protocol was optimized and the chemical composition of the high molecular weight fraction (>10 kDa) was evaluated, by analyzing the content of protein, caffeine, chlorogenic acid, and the total dietary fiber. In addition, the structural analysis was performed by infrared spectroscopy. Antioxidant properties were studied in vitro and the fiber effect was studied in vivo, in healthy male Wistar rats. Melanoidins were administered to animals in the drinking water at a dose of 1 g/kg. At the fourth week of treatment, gastrointestinal motility was evaluated through non-invasive radiographic means. In conclusion, the isolation process was effective in obtaining a high molecular weight fraction, composed mainly of dietary fiber, including melanoidins, with in vitro antioxidant capacity and in vivo dietary fiber effects.

14.
Neurogastroenterol Motil ; 31(3): e13499, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30402956

RESUMO

BACKGROUND: Cisplatin is a highly emetogenic antineoplastic drug and induces peripheral neuropathy when given in cycles. Granisetron, a 5-HT3 antagonist, is clinically used to prevent chemotherapy-induced nausea/emesis and abdominal pain in irritable bowel syndrome. The effects of cisplatin on visceral sensitivity and those of granisetron in the context of cancer chemotherapy are not well known. METHODS: Adult male Wistar rats received two intraperitoneal injections 30 minutes apart: granisetron (1 mg kg-1 )/vehicle and cisplatin (6 mg kg-1 )/vehicle. Thereafter, nausea-like behavior was measured as bedding intake for 4 hours, and gastric dysmotility was measured radiographically for 8 hours. Gastric weight and size were determined ex vivo and samples of the forestomach, corpus, ileum, and colon were obtained for histological analysis at 4 and 30 hours after cisplatin/vehicle. Visceral sensitivity was measured as abdominal contractions in response to mechanical intracolonic stimulation 2 hours after cisplatin/vehicle. KEY RESULTS: Cisplatin-induced bedding intake and gastric dysmotility, and granisetron blocked these effects, which occurred in the absence of frank mucositis. Visceral sensitivity was reduced to a similar extent by both drugs alone or in combination. CONCLUSIONS AND INFERENCES: Cisplatin-induced bedding intake and gastric dysmotility were blocked by granisetron, confirming the involvement of serotonin acting on 5-HT3 receptors. Unexpectedly, visceral sensitivity to colonic distension was reduced, to the same extent, by cisplatin, granisetron, and their combination, suggesting important mechanistic differences with nausea and gastric dysmotility that warrant further investigation.


Assuntos
Antieméticos/farmacologia , Antineoplásicos/farmacologia , Cisplatino/antagonistas & inibidores , Cisplatino/farmacologia , Colo/efeitos dos fármacos , Motilidade Gastrointestinal/efeitos dos fármacos , Granisetron/farmacologia , Antagonistas da Serotonina/farmacologia , Estômago/efeitos dos fármacos , Animais , Colo/patologia , Masculino , Náusea/induzido quimicamente , Náusea/psicologia , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Wistar , Estômago/patologia
15.
Eur J Pain ; 23(3): 603-620, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30376213

RESUMO

BACKGROUND: The antineoplastic drugs cisplatin and vincristine induce peripheral neuropathies. The sigma-1 receptor (σ1R) is expressed in areas of pain control, and its blockade with the novel selective antagonist MR-309 has shown efficacy in nociceptive and neuropathic pain models. Our goal was to test whether this compound reduces neuropathic signs provoked by these antitumoural drugs. METHODS: Rats were treated with cisplatin or vincristine to induce neuropathies. The effects of acute or repeated administration of MR-309 were tested on mechanical and thermal sensitivity, electrophysiological activity of Aδ-primary afferents in the rat skin-saphenous nerve preparation, and gastrointestinal or cardiovascular functions. RESULTS: Rats treated with antitumourals developed tactile allodynia, while those treated with vincristine also developed mechanical hyperalgesia. These in vivo modifications correlated with electrophysiological hyperactivity (increased spontaneous activity and hyperresponsiveness to innocuous and noxious mechanical stimulation). Animals treated with cisplatin showed gastrointestinal impairment and those receiving vincristine showed cardiovascular toxicity. A single dose of MR-309 strongly reduced both nociceptive behaviour and electrophysiological changes. Moreover, its concomitant administration with the antitumourals blocked the development of neuropathic symptoms, thus restoring mechanical sensitivity, improving the impairment of feeding behaviour and gastrointestinal transit in the cisplatin-treated group along with ameliorating the altered vascular reactivity recorded in rats treated with vincristine. CONCLUSION: σ1R antagonist, MR-309, reduces sensorial and electrophysiological neuropathic signs in rats treated with cisplatin or vincristine and, in addition, reduces gastrointestinal and cardiovascular side effects. SIGNIFICANCE: σ1R antagonism could be an interesting and new option to palliate antitumoural neuropathies.


Assuntos
Cisplatino/efeitos adversos , Hiperalgesia/tratamento farmacológico , Morfolinas/uso terapêutico , Neuralgia/tratamento farmacológico , Pirazóis/uso terapêutico , Receptores sigma/antagonistas & inibidores , Vincristina/efeitos adversos , Animais , Antineoplásicos/efeitos adversos , Modelos Animais de Doenças , Hiperalgesia/induzido quimicamente , Masculino , Neuralgia/induzido quimicamente , Ratos , Ratos Sprague-Dawley
18.
Behav Pharmacol ; 29(2 and 3-Spec Issue): 103-119, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29521671

RESUMO

In recent years, interest in the relationship between gut microbiota and disease states has grown considerably. Indeed, several strategies have been employed to modify the microbiome through the administration of different diets, by the administration of antibiotics or probiotics, or even by transplantation of feces. In the present manuscript, we focus specifically on the potential application of probiotics, which seem to be a safe strategy, in the management of digestive, pain, and emotional disorders. We present evidence from animal models and human studies, notwithstanding that translation to clinic still deserves further investigation. The microbiome influences gut functions as well as neurological activity by a variety of mechanisms, which are also discussed. The design and performance of larger trials is urgently needed to verify whether these new strategies might be useful not only for the treatment of disorders affecting the gastrointestinal tract but also in the management of emotional and pain disorders not directly related to the gut.


Assuntos
Microbioma Gastrointestinal/fisiologia , Probióticos/farmacologia , Probióticos/uso terapêutico , Animais , Sistema Digestório/efeitos dos fármacos , Emoções/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Dor/dietoterapia , Dor/tratamento farmacológico
19.
Behav Pharmacol ; 29(2 and 3-Spec Issue): 120-139, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29543647

RESUMO

Beyond their well-known role in embryonic development of the central and peripheral nervous system, neurotrophins, particularly nerve growth factor and brain-derived neurotrophic factor, exert an essential role in pain production and sensitization. This has mainly been studied within the framework of somatic pain, and even antibodies (tanezumab and fasinumab) have recently been developed for their use in chronic somatic painful conditions, such as osteoarthritis or low back pain. However, data suggest that neurotrophins also exert an important role in the occurrence of visceral pain and visceral sensitization. Visceral pain is a distressing symptom that prompts many consultations and is typically encountered in both 'organic' (generally inflammatory) and 'functional' (displaying no obvious structural changes in routine clinical evaluations) disorders of the gut, such as inflammatory bowel disease and irritable bowel syndrome, respectively. The present review provides a summary of neurotrophins as a molecular family and their role in pain in general and addresses recent investigations of the involvement of nerve growth factor and brain-derived neurotrophic factor in visceral pain, particularly that associated with inflammatory bowel disease and irritable bowel syndrome.


Assuntos
Fatores de Crescimento Neural/farmacologia , Fatores de Crescimento Neural/fisiologia , Dor Visceral/fisiopatologia , Animais , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Humanos , Hiperalgesia/metabolismo , Síndrome do Intestino Irritável , Fator de Crescimento Neural/fisiologia
20.
Curr Med Chem ; 25(16): 1879-1908, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29210639

RESUMO

BACKGROUND: Guanylate cyclase C (GC-C) receptor is a transmembrane receptor, predominantly expressed in intestinal epithelial cells, which is considered to play a main role in homeostasis and function of the digestive tract. The endogenous ligands for this receptor are the paracrine hormones uroguanylin and guanylin. Upon ligand binding, GC-C receptors increase cyclic guanosine monophosphate (cGMP) levels, regulating a variety of key cell-type specific processes such as chloride and bicarbonate secretion, epithelial cell growth, regulation of intestinal barrier integrity and visceral sensitivity. It has been suggested that GC-C acts as an intestinal tumor suppressor with the potential to prevent the initiation and progression of colorectal cancer. In fact, loss of ligand expression is a universal step in sporadic colorectal carcinogenesis. Interestingly, the role of GC-C is not limited to the digestive tract but it has been extended to several other systems such as the cardiovascular system, kidney, and the central nervous system, where it has been involved in a gut-hypothalamus endocrine axis regulating appetite. Objetive: In this review we summarize the physiology of the GC-C receptor and its ligands, focusing on newly developed drugs like linaclotide, and their suggested role to reverse/prevent the diseases in which the receptor is involved. CONCLUSION: Available data points toward a relationship between uroguanylin and guanylin and their receptor and pathological processes like gastrointestinal and renal disorders, colorectal cancer, obesity, metabolic syndrome and mental disorders among others. Recent pharmacological developments in the regulation of GC-receptor may involve further improvements in the treatment of relevant diseases.


Assuntos
GMP Cíclico/metabolismo , Guanilato Ciclase/metabolismo , Receptores de Peptídeos/metabolismo , Animais , Neoplasias Colorretais/terapia , Hormônios Gastrointestinais/metabolismo , Humanos , Doenças Inflamatórias Intestinais/terapia , Mucosa Intestinal/metabolismo , Nefropatias/terapia , Peptídeos Natriuréticos/metabolismo , Obesidade/terapia , Ligação Proteica , Transporte Proteico , Transdução de Sinais
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...