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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.
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
3.
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
4.
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
5.
Sci Rep ; 9(1): 1868, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755648

RESUMO

Aluminum (Al), which is omnipresent in human life, is a potent neurotoxin. Here, we have tested the potential for Egg White Hydrolysate (EWH) to protect against changes in cognitive function in rats exposed to both high and low levels of Al. Indeed, EWH has been previously shown to improve the negative effects induced by chronic exposure to heavy metals. Male Wistar rats received orally: Group 1) Low aluminum level (AlCl3 at a dose of 8.3 mg/kg b.w. during 60 days) with or without EWH treatment (1 g/kg/day); Group 2) High aluminum level (AlCl3 at a dose of 100 mg/kg b.w. during 42 days) with or without EWH treatment (1 g/kg/day). After 60 or 42 days of exposure, rats exposed to Al and EWH did not show memory or cognitive dysfunction as was observed in Al-treated animals. Indeed, co-treatment with EWH prevented catalepsy, hippocampal oxidative stress, cholinergic dysfunction and increased number of activated microglia and COX-2-positive cells induced by Al exposure. Altogether, since hippocampal inflammation and oxidative damage were partially prevented by EWH, our results suggest that it could be used as a protective agent against the detrimental effects of long term exposure to Al.


Assuntos
Alumínio/toxicidade , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/prevenção & controle , Clara de Ovo , Alimento Funcional , Hidrolisados de Proteína/uso terapêutico , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/metabolismo , Comportamento Animal , Peso Corporal , Ciclo-Oxigenase 2/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Memória de Longo Prazo/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
6.
Nutrients ; 10(10)2018 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-30322196

RESUMO

Metabolic syndrome (MetS) is defined as a constellation of many metabolic disorders such as hypertension, impaired glucose tolerance, dyslipidemia and obesity, being this last disorder a key factor in the etiology of the syndrome. The widespread of MetS in actual society, mainly in developed countries, is becoming an important health problem and is increasing the need to develop new treatments against this pathology is increasing fast. The main objective of the present study was to evaluate the MetS-associated alterations developed in a new glucose diet-induced-obesity (DIO) rodent model. These alterations were also compared to those alterations developed in a fructose-DIO rodent model. Wistar rats were divided into four groups: Control (C), High-fat (HF), High-fat/high-fructose (HFF) and High-fat/high-glucose (HFG). The animals were fed ad libitum for 20 weeks. At the end of the study, HFG animals showed lower expression of energy expenditure genes when compared to the other DIO groups. Oxidative stress biomarkers such as MDA and mitochondrial RT-qPCR analyses showed an increase of oxidative damage together with mitochondrial dysfunction in HFG group. This group also showed increased insulin and glucose plasma levels, though HFF animals showed the greatest increase on these parameters. All DIO groups showed increased plasma levels of triglycerides. Altogether, our results indicated a better impact of glucose than fructose, when combined with a high-fat diet, to induce most of the alterations associated with MetS in rats. In addition, our research facilitates a new animal model to evaluate future treatments for MetS.


Assuntos
Dieta Hiperlipídica , Açúcares da Dieta , Metabolismo Energético , Frutose , Glucose , Síndrome Metabólica/etiologia , Adiponectina/sangue , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Modelos Animais de Doenças , Metabolismo Energético/genética , Regulação da Expressão Gênica , Insulina/sangue , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/genética , Síndrome Metabólica/fisiopatologia , Estresse Oxidativo , Ratos Wistar , Triglicerídeos/sangue , Ganho de Peso
7.
Nutrients ; 10(4)2018 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-29614007

RESUMO

The purpose of this study was to evaluate the effect of the administration of two egg white hydrolysates on glucose metabolism complications related to Metabolic Syndrome (MS) in Zucker fatty rats (ZFR). ZFR were given 750 mg/kg/day of egg white hydrolyzed with pepsin (HEW1) or with aminopeptidase (HEW2) for 12 weeks in their drinking water or just water. Zucker lean rats (ZLR), which received water, were used as a control. The presence of tactile allodynia, which is a sign of peripheral neuropathy, was assessed. Blood samples and pancreas were collected to determine the effect of the hydrolysates on glucose metabolism. The intake of HEW1 significantly lowered plasma insulin levels and improved the quantitative indexes of insulin resistance, insulin sensitivity, and pancreatic ß-cell functionality (HOMA-IR, HOMA-ß, and QUICKI, respectively), but non-significant changes were observed in group treated with HEW2. Compared to ZLR, ZFR showed tactile allodynia, but the consumption of both hydrolysates significantly increased mechanical sensitivity in ZFR. In conclusion, HEW1 pepsin could improve the glucose metabolism abnormalities associated with MS in obese Zucker rats.


Assuntos
Glicemia/metabolismo , Clara de Ovo , Resistência à Insulina , Insulina/sangue , Síndrome Metabólica/complicações , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Hidrolisados de Proteína/uso terapêutico , Animais , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Células Secretoras de Insulina/efeitos dos fármacos , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/fisiopatologia , Ovalbumina/metabolismo , Ovalbumina/farmacologia , Ovalbumina/uso terapêutico , Pepsina A/metabolismo , Doenças do Sistema Nervoso Periférico/etiologia , Hidrolisados de Proteína/farmacologia , Ratos Zucker
8.
J Inorg Biochem ; 181: 169-176, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28865725

RESUMO

Aluminum (Al) is a neurotoxic associated with a number of chronic human diseases. We investigated the effects of Al exposure at doses similar to human dietary levels and at a high level exposure to Al on the peripheral nervous system. Wistar male rats were divided into two major groups and received orally: 1) First group - Low level - rats were subdivided and treated for 60days: a) Control - received ultrapure water; b) AlCl3 - received Al at 8.3mg/kg body weight (bw) for 60days; and 2) Second group - High level - rats were subdivided and treated for 42days: C) Control - received ultrapure water through oral gavage; d) AlCl3 - received Al at 100mg/kg bw for 42days. Von Frey hair test, plantar test, the presence of catalepsy and the spontaneous motor activity were investigated. Reactive oxygen species, lipid peroxidation and total antioxidant capacity, immunohistochemistry to investigate the nerve inflammation and, the specific presence of Al in the sciatic nerve fibers were investigated. Al exposure at a representative human dietary level promotes the development of mechanical allodynia, catalepsy, increased inflammation in the sciatic nerve, systemic oxidative stress and, is able to be retained in the sciatic nerve. The effects of low-dose Al were similar to those found in rats exposed to Al at a dose much higher (100mg/kg). Our findings suggest that Al may be considered toxic for the peripheral nervous system, thus inducing peripheral dysfunction.


Assuntos
Alumínio/toxicidade , Neurite (Inflamação)/etiologia , Síndromes Neurotóxicas/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/etiologia , Sistema Nervoso Periférico/efeitos dos fármacos , Poluentes da Água/toxicidade , Alumínio/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Catalepsia/etiologia , Relação Dose-Resposta a Droga , Hiperalgesia/etiologia , Peroxidação de Lipídeos/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Neurite (Inflamação)/imunologia , Neurite (Inflamação)/metabolismo , Neurite (Inflamação)/fisiopatologia , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/patologia , Sistema Nervoso Periférico/imunologia , Sistema Nervoso Periférico/fisiopatologia , Doenças do Sistema Nervoso Periférico/imunologia , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/fisiopatologia , Ratos Wistar , Espécies Reativas de Oxigênio/sangue , Espécies Reativas de Oxigênio/metabolismo , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/imunologia , Nervo Isquiático/metabolismo , Nervo Isquiático/patologia , Fatores de Tempo , Distribuição Tecidual , Testes de Toxicidade Crônica , Toxicocinética , Poluentes da Água/administração & dosagem
9.
Front Pharmacol ; 8: 37, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28220074

RESUMO

Background: In different models of paralytic ileus, cannabinoid receptors are overexpressed and endogenous cannabinoids are massively released, contributing to gastrointestinal dysmotility. The antitumoral drug vincristine depresses gastrointestinal motility and a similar mechanism could participate in this effect. Therefore, our aim was to determine, using CB1 and CB2 antagonists, whether an increased endocannabinoid tone is involved in vincristine-induced gastrointestinal ileus. Methods: First, we confirmed the effects of vincristine on the gut mucosa, by conventional histological techniques, and characterized its effects on motility, by radiographic means. Conscious male Wistar rats received an intraperitoneal injection of vincristine (0.1-0.5 mg/kg), and barium sulfate (2.5 ml; 2 g/ml) was intragastrically administered 0, 24, or 48 h later. Serial X-rays were obtained at different time-points (0-8 h) after contrast. X-rays were used to build motility curves for each gastrointestinal region and determine the size of stomach and caecum. Tissue samples were taken for histology 48 h after saline or vincristine (0.5 mg/kg). Second, AM251 (a CB1 receptor antagonist) and AM630 (a CB2 receptor antagonist) were used to determine if CB1 and/or CB2 receptors are involved in vincristine-induced gastrointestinal dysmotility. Key results: Vincristine induced damage to the mucosa of ileum and colon and reduced gastrointestinal motor function at 0.5 mg/kg. The effect on motor function was particularly evident when the study started 24 h after administration. AM251, but not AM630, significantly prevented vincristine effect, particularly in the small intestine, when administered thrice. AM251 alone did not significantly alter gastrointestinal motility. Conclusions: The fact that AM251, but not AM630, is capable of reducing the effect of vincristine suggests that, like in other experimental models of paralytic ileus, an increased cannabinoid tone develops and is at least partially responsible for the alterations induced by the antitumoral drug on gastrointestinal motor function. Thus, CB1 antagonists might be useful to prevent/treat ileus induced by vincristine.

10.
Brain Res ; 1646: 482-489, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27350078

RESUMO

This study aims to investigate whether the egg white hydrolysate (EWH) acts on the neuropathic disorders associated with long-term Mercury (Hg) exposure in rats. 8- week-old male Wistar rats were treated for 60 days with: a) Control - saline solution (i.m.); b) Mercury - HgCl2 (1st dose 4.6µg/kg, subsequent doses 0.07µg/kg/day, i.m.); c) Hydrolysate - EWH (1g/kg/day, gavage); d) Mercury and Hydrolysate. Mechanical allodynia was assessed using Von Frey Hairs test; heat hyperalgesia by the plantar test; catalepsy by a modification of the "ring test" and spontaneous locomotor activity by a photocell activity chambers. Analyses were performed at 0, 30 and 60 days of treatment. Brain and plasma MDA, plasma NPSH and TNF-α determination and skin immunohistochemistry were performed at 60 days. Hg induced a reduction in mechanical sensitivity threshold at 30 and 60 days and in thermal sensitivity threshold at 60 days. At the end of treatment catalepsy was developed, but there was not significant alteration in spontaneous locomotor activity. Hg also increased brain and plasma MDA, plasma NPSH and TNF-α levels and the number of Merkel cell-neurite complex in the skin. EWH prevented the development of mechanical allodynia, thermal hyperalgesia and catalepsy induced by Hg and the increase in MDA concentration in brain and plasma and in the number of Merkel cell-neurite complex in the skin. In conclusion, EWH promotes neuroprotection against the toxic effects caused by Hg, demonstrating a beneficial therapeutic potential.


Assuntos
Mercúrio/toxicidade , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/complicações , Hidrolisados de Proteína/administração & dosagem , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Catalepsia/induzido quimicamente , Catalepsia/etiologia , Catalepsia/prevenção & controle , Clara de Ovo/química , Hiperalgesia/induzido quimicamente , Hiperalgesia/etiologia , Hiperalgesia/prevenção & controle , Peroxidação de Lipídeos/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Células de Merkel/metabolismo , Neuritos/metabolismo , Hidrolisados de Proteína/isolamento & purificação , Ratos , Ratos Wistar , Pele/metabolismo , Pele/patologia
11.
Exp Brain Res ; 232(8): 2601-12, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24798399

RESUMO

Cancer chemotherapy is associated with the development of numerous adverse effects, including nausea, emesis and other alterations in gastrointestinal (GI) motility. The administration of 5-HT3 receptor antagonists has provided a clinical advance in the treatment of chemotherapy-induced vomiting but these drugs lose efficacy throughout chronic treatment. The effects of these drugs in experimental animals under chronic administration are not well known. Our aim was to study, using radiographic methods, the effect of the 5-HT3 receptor antagonist granisetron on GI dysmotility induced in the rat by repeated cisplatin administration. First, invasive methods were used to select a dose of granisetron capable of reducing increased stomach weight due to acute cisplatin administration (6 mg/kg, ip). Second, rats received two intraperitoneal (ip) injections once a week for 4 weeks: granisetron (1 mg/kg, ip) or saline and, thirty min later, saline or cisplatin (2 mg/kg, ip). Body weight gain was measured throughout treatment. Radiological techniques were used to determine the acute (after first dose) and chronic (after last dose) effects of cisplatin and/or granisetron on GI motility. Repeated cisplatin-induced weight loss which granisetron did not prevent. Gastric emptying was delayed after the first cisplatin administration. Granisetron completely prevented this effect. After weekly administration, cisplatin-induced gastric dysmotility was enhanced and granisetron was not capable of completely preventing this effect. Granisetron prevents gastric emptying alterations, but its efficacy decreases throughout antineoplastic treatment. This might be due to the enhanced effect of cisplatin.


Assuntos
Antieméticos/farmacologia , Antineoplásicos/farmacologia , Cisplatino/farmacologia , Motilidade Gastrointestinal/efeitos dos fármacos , Granisetron/farmacologia , Raios X , Análise de Variância , Animais , Peso Corporal/efeitos dos fármacos , Meios de Contraste , Esvaziamento Gástrico/efeitos dos fármacos , Masculino , Radiografia , Ratos , Ratos Wistar , Fatores de Tempo , Trato Gastrointestinal Superior/diagnóstico por imagem , Trato Gastrointestinal Superior/efeitos dos fármacos
12.
Pharmacol Biochem Behav ; 105: 205-12, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23454533

RESUMO

Clinical use of antineoplastic drugs is associated with the development of numerous adverse effects that many patients find intolerable, including peripheral neuropathy. Cannabinoids have relieved neuropathic pain in different animal models. But their therapeutic activities could be affected by their psychoactive properties. The aim of this work was to determine the effect of cannabinoids in cisplatin-evoked neuropathy. For this purpose, the non-selective agonist WIN 55,212-2 (WIN), the CB1-selective agonist ACEA or the CB2-selective agonist JWH133 (or their vehicle) was either systemically administered at a non-psychoactive dose or locally injected in cisplatin-treated rats. Selective CB1 and CB2 cannabinoid antagonists (AM251 and SR144528, respectively) were used to characterize cannabinoid effects. Cisplatin-treated rats showed mechanical allodynia but not thermal hyperalgesia. Cannabinoid agonists alleviated mechanical allodynia. This effect was mediated by both CB1 and CB2 cannabinoid receptors when the cannabinoid was systemically applied. At the dose used, cannabinoid agonists had no psychoactive effect. The local effect of the drug involved the activation of peripheral CB1 receptors whereas involvement of CB2 receptors was less clear. In a rat model of cisplatin-induced neuropathy, cannabinoids have an antinociceptive effect, but the cannabinoid receptors involved could be different depending on the route of administration. Non-psychoactive doses of cannabinoid agonists are capable of alleviating the signs of peripheral neuropathy when systemically applied. Interestingly, local administration of selective CB1 agonists or systemic administration of CB2 agonists, which are non-psychoactive, may serve as new therapeutic alternatives for symptom management in painful neuropathy associated with cisplatin treatment.


Assuntos
Antineoplásicos/efeitos adversos , Canabinoides/uso terapêutico , Cisplatino/efeitos adversos , Neuralgia/tratamento farmacológico , Animais , Modelos Animais de Doenças , Masculino , Neuralgia/induzido quimicamente , Ratos , Ratos Wistar
13.
Pharmacology ; 90(1-2): 1-10, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22699400

RESUMO

The marijuana plant Cannabis sp. and its derivatives and analogues, known as cannabinoids (CBs), induce many effects throughout the whole body. Herein we briefly review the gastrointestinal (GI) pharmacology of CBs, with special focus on motor function. Some drugs are available to treat nausea and emesis, and evidences in humans and animal models suggest that other GI motility alterations (gastro-oesophageal reflux, inflammatory bowel conditions or paralytic ileus) might benefit from modifications of the CB tone throughout the gut. However, central and peripheral (including GI) side effects may occur upon acute and chronic CB administration. Hopefully, the ongoing worldwide intense research on CBs will soon provide new, safer CB-based medicines.


Assuntos
Canabinoides/farmacologia , Trato Gastrointestinal/efeitos dos fármacos , Animais , Canabinoides/uso terapêutico , Gastroenteropatias/tratamento farmacológico , Gastroenteropatias/fisiopatologia , Motilidade Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/fisiologia , Humanos
14.
Pharmacol Biochem Behav ; 102(2): 335-43, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22609797

RESUMO

Diabetic neuropathy is a frequent complication of diabetes mellitus with a tremendous impact on patients' quality of life, and it remains poorly treated. Cannabinoids relieve the signs of diabetic neuropathy in different experimental models, including streptozotocin- (STZ-) induced type 1 diabetic rodents, and they may also relieve neuropathic signs in type 2 diabetic animals. This study compares the effect of the non-selective cannabinoid agonist WIN 55,212-2 (WIN) in Zucker Diabetic Fatty (ZDF) rats (type 2 diabetes) and in STZ-injected Wistar rats (type 1 diabetes). WIN (or its vehicle) was either systemically administered at a non-psychoactive dose or locally injected. Selective CB1 and CB2 cannabinoid antagonists were used to characterize WIN antineuropathic effects. Both type 1 and type 2 diabetic rats showed mechanical allodynia but not thermal hyperalgesia. WIN alleviated mechanical allodynia in both models of diabetes. In STZ-treated rats, both cannabinoid receptors were involved, whereas in ZDF rats, WIN effects seemed to mainly involve the activation of CB1 receptors. Higher doses of WIN were needed to significantly relieve mechanical allodynia upon intraplantar administration in ZDF vs. STZ-injected rats. Cannabinoids, acting on systemic and/or peripheral receptors, may serve as a new therapeutic alternative for symptom management in painful neuropathy associated with both type 1 and type 2 diabetes. Additionally, our results highlight the need for appropriate selection of diabetic experimental models because the results from studies in STZ-induced diabetic rodents might not be applicable in all diabetic situations.


Assuntos
Benzoxazinas/uso terapêutico , Canabinoides/uso terapêutico , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Morfolinas/uso terapêutico , Naftalenos/uso terapêutico , Neuralgia/tratamento farmacológico , Animais , Modelos Animais de Doenças , Neuralgia/etiologia , Ratos , Ratos Wistar , Ratos Zucker
15.
Rev Neurol ; 54(6): 349-56, 2012 Mar 16.
Artigo em Espanhol | MEDLINE | ID: mdl-22403148

RESUMO

INTRODUCTION: Resveratrol is a polyphenol present in grapes, some nuts and dried fruits, and red wine. A number of beneficial properties have been attributed to this compound. Its potential neuroprotective effects are the subject of much research today. AIM: To review the effects of resveratrol, and more particularly those related to its capacity to offer protection against the neurodegeneration associated with several pathologies and traumatic injuries in the central nervous system. DEVELOPMENT: It has been suggested that the daily consumption of red wine, and therefore of resveratrol, could account for the so-called 'French paradox', according to which the population in the south of France, despite eating a diet that is relatively high in saturated fats, presents a low risk of heart disease. From this first evidence of the cardioprotective properties of resveratrol, its study has been extended and equally attractive biopharmacological effects have now been found in many different fields. Thus, neuroprotective effects have been found in models of neurodegeneration (Alzheimer's, Parkinson's or Huntington's disease, or diverse neuropathies), of ischaemia and of brain and spinal cord injury, but further clinical data are still needed in this regard. CONCLUSIONS: Although few studies have been conducted in humans, recent findings in experimental models of neurological pathology are encouraging and open up the doors to future clinical studies that will allow the therapeutic value of resveratrol to be determined.


Assuntos
Transtornos Cerebrovasculares/prevenção & controle , Dieta Mediterrânea , Doenças Neurodegenerativas/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Estilbenos/uso terapêutico , Peptídeos beta-Amiloides/metabolismo , Animais , Antioxidantes/administração & dosagem , Antioxidantes/uso terapêutico , Disponibilidade Biológica , Cardiotônicos/administração & dosagem , Cardiotônicos/uso terapêutico , Sobrevivência Celular , Reparo do DNA , Humanos , Proteínas do Tecido Nervoso/fisiologia , Fármacos Neuroprotetores/administração & dosagem , Doenças do Sistema Nervoso Periférico/prevenção & controle , Traumatismo por Reperfusão/prevenção & controle , Resveratrol , Sirtuína 1/fisiologia , Medula Espinal/irrigação sanguínea , Estilbenos/administração & dosagem , Estilbenos/química , Estilbenos/farmacocinética , Traumatismos do Sistema Nervoso/tratamento farmacológico , Vitis/química , Vinho/análise
16.
Rev. neurol. (Ed. impr.) ; 54(6): 349-356, 16 mar., 2012. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-99557

RESUMO

Introducción. El resveratrol es un polifenol presente en las uvas, algunos frutos secos y el vino tinto. Se han atribuido numerosas propiedades beneficiosas a este compuesto. Sus potenciales efectos neuroprotectores son objeto de numerosos estudios en la actualidad. Objetivo. Revisar los efectos del resveratrol, en particular los relacionados con su capacidad para proteger frente a la neurodegeneración asociada a diversas patologías y a lesiones traumáticas en el sistema nervioso central. Desarrollo. Se ha sugerido que el consumo diario de cantidades moderadas de vino tinto y, por tanto, de resveratrol, explicaría la llamada ‘paradoja francesa’, según la cual la población del sur de Francia, a pesar de consumir una dieta relativamente alta en grasas saturadas, presenta un reducido riesgo de enfermedad coronaria. A partir de estas primeras evidencias de las propiedades cardioprotectoras del resveratrol, se ha extendido su estudio y ya son muchos los campos en los que se han encontrado efectos biofarmacológicos igualmente atractivos, incluyendo efectos neuroprotectores en modelos de neurodegeneración (enfermedad de Alzheimer, de Parkinson o de Huntington, o neuropatías diversas), de isquemia y de lesión cerebral y medular, pero aún faltan estudios clínicos en este sentido. Conclusiones. Aunque los estudios en humanos aún son escasos, los recientes resultados encontrados en los modelos experimentales de patología neurológica son alentadores y abren la puerta a futuros estudios clínicos que permitan determinar la utilidad terapéutica del resveratrol (AU)


Introduction. Resveratrol is a polyphenol present in grapes, some nuts and dried fruits, and red wine. A number of beneficial properties have been attributed to this compound. Its potential neuroprotective effects are the subject of much research today. Aim. To review the effects of resveratrol, and more particularly those related to its capacity to offer protection against the neurodegeneration associated with several pathologies and traumatic injuries in the central nervous system. Development. It has been suggested that the daily consumption of red wine, and therefore of resveratrol, could account for the so-called ‘French paradox’, according to which the population in the south of France, despite eating a diet that is relatively high in saturated fats, presents a low risk of heart disease. From this first evidence of the cardioprotective properties of resveratrol, its study has been extended and equally attractive biopharmacological effects have now been found in many different fields. Thus, neuroprotective effects have been found in models of neurodegeneration (Alzheimer’s, Parkinson’s or Huntington’s disease, or diverse neuropathies), of ischaemia and of brain and spinal cord injury, but further clinical data are still needed in this regard. Conclusions. Although few studies have been conducted in humans, recent findings in experimental models of neurological pathology are encouraging and open up the doors to future clinical studies that will allow the therapeutic value of resveratrol to be determined (AU)


Assuntos
Humanos , Dieta Mediterrânea , Polifenóis/farmacocinética , Doenças Neurodegenerativas/dietoterapia , Sirtuínas/metabolismo , Lesões Encefálicas Traumáticas/dietoterapia , Traumatismos da Medula Espinal/dietoterapia , Fármacos Neuroprotetores
17.
Diabetes Metab Res Rev ; 27(4): 331-40, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21309057

RESUMO

BACKGROUND: Diabetes increases cardiac damage after myocardial ischaemia. Cannabinoids can protect against myocardial ischaemia/reperfusion injury. The aim of this study was to examine the cardioprotective effect of the cannabinoid agonist WIN 55,212-2 (WIN) against ischaemia/reperfusion injury in an experimental model of type 2 diabetes. We performed these experiments in the Zucker diabetic fatty rat, and focused on the role of cannabinoid receptors in modulation of cardiac inducible nitric oxide synthase (iNOS)/endothelial-type nitric oxide synthase (eNOS) expression. METHODS: Male 20-week-old Zucker diabetic fatty rats were treated with vehicle, WIN, the selective CB1 or CB2 receptor antagonists AM251 and AM630, respectively, AM251 + WIN or AM630 + WIN. Hearts were isolated from these rats, and the cardiac functional response to ischaemia/reperfusion injury was evaluated. In addition, cardiac iNOS and eNOS expression were determined by western blot. RESULTS: WIN significantly improved cardiac recovery after ischaemia/ reperfusion in the hearts from Zucker diabetic fatty rats by restoring coronary perfusion pressure and heart rate to preischaemic levels. Additionally, WIN decreased cardiac iNOS expression and increased eNOS expression after ischaemia/reperfusion in diabetic hearts. WIN-induced cardiac functional recovery was completely blocked by the CB2 antagonist AM630. However, changes in NOS isoenzyme expression were not affected by the CB antagonists. CONCLUSIONS: This study shows a cardioprotective effect of a cannabinoid agonist on ischaemia/reperfusion injury in an experimental model of a metabolic disorder. The activation mainly of CB2 receptors and the restoration of iNOS/eNOS cardiac equilibrium are mechanisms involved in this protective effect. These initial studies have provided the basis for future research in this field.


Assuntos
Benzoxazinas/uso terapêutico , Canabinoides/uso terapêutico , Cardiotônicos/uso terapêutico , Morfolinas/uso terapêutico , Isquemia Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Naftalenos/uso terapêutico , Receptor CB2 de Canabinoide/agonistas , Animais , Benzoxazinas/antagonistas & inibidores , Canabinoides/antagonistas & inibidores , Cardiotônicos/antagonistas & inibidores , Vasos Coronários/efeitos dos fármacos , Diabetes Mellitus Tipo 2/complicações , Coração/efeitos dos fármacos , Coração/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Indóis/farmacologia , Masculino , Morfolinas/antagonistas & inibidores , Isquemia Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Naftalenos/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Zucker , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/metabolismo
18.
Neurosci Lett ; 467(2): 105-10, 2009 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-19819299

RESUMO

Gastrointestinal motility is mainly controlled by the myenteric plexus. The longitudinal muscle-myenteric plexus (LMMP) preparation from the guinea-pig ileum is the best characterised adult gastrointestinal preparation; it has also been studied in old and neonatal animals, but not at weaning, when milk is substituted with the food typical of adult animals. We used LMMP preparations from weanling and adult guinea-pigs to study different functional parameters and immunohistochemically identified subpopulations of myenteric neurones, including the excitatory motor neurones to the longitudinal muscle (LM-EMN). Excitatory stimuli (low-frequency electrical stimulation, acetylcholine, substance P, and naloxone in morphine-tolerant preparations) produced similar responses in weanling and adult guinea-pigs. The endogenous cannabinoid anandamide, but not the synthetic cannabinoid agonist WIN 55,212-2 or the opioid morphine, inhibited the electrically stimulated twitches less efficaciously, and in vitro tolerance to morphine was also lower in weanling compared to adult animals. The packing densities of the calbindin-immunoreactive neurones (sensory neurones) and of neurones immunoreactive to both calretinin (CR) and neurofilament triplet protein (NFT; ascending interneurones) were slightly but significantly lower in weanling animals, whereas those of the neurones immunoreactive to CR but not NFT (LM-EMN) or immunoreactive to nitric oxide synthase (mainly inhibitory motor neurones) were comparable to the adult. Although guinea-pigs are relatively mature and can even ingest solid food at birth, their myenteric plexus is still not fully mature at the standard time of weaning. The nutritional, behavioural and environmental changes associated with weaning may be essential to attain full maturation of the myenteric plexus and gastrointestinal motility.


Assuntos
Íleo/crescimento & desenvolvimento , Plexo Mientérico/crescimento & desenvolvimento , Acetilcolina/farmacologia , Animais , Ácidos Araquidônicos/farmacologia , Benzoxazinas/farmacologia , Calbindina 2 , Calbindinas , Agonistas Colinérgicos/farmacologia , Estimulação Elétrica , Endocanabinoides , Feminino , Cobaias , Íleo/inervação , Íleo/fisiologia , Imuno-Histoquímica , Morfina/farmacologia , Morfolinas/farmacologia , Contração Muscular , Músculo Liso/inervação , Músculo Liso/fisiologia , Plexo Mientérico/efeitos dos fármacos , Plexo Mientérico/fisiologia , Naloxona/farmacologia , Naftalenos/farmacologia , Antagonistas de Entorpecentes/farmacologia , Proteínas de Neurofilamentos/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Alcamidas Poli-Insaturadas/farmacologia , Receptor CB1 de Canabinoide/agonistas , Receptores Opioides/agonistas , Proteína G de Ligação ao Cálcio S100/metabolismo , Substância P/farmacologia , Desmame
19.
Auton Neurosci ; 141(1-2): 54-65, 2008 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-18579450

RESUMO

Nausea and vomiting are amongst the most severe dose-limiting side effects of chemotherapy. Emetogenic activity in rats can only be evaluated by indirect markers, such as pica (kaolin intake), or delay in gastric emptying. The aim of this work was to study, by radiological methods, the alterations in gastrointestinal motility induced by acute cisplatin in the rat, and to compare them with the development of pica. Rats received cisplatin (0-6 mg kg(-1)) at day 0. In the pica study, individual food ingestion and kaolin intake were measured each day (from day -3 to day 3). In the radiological study, conscious rats received an intragastric dose of medium contrast 0, 24 or 48 h after cisplatin injection, and serial X-rays were taken 0-24 h after contrast. Cisplatin dose-dependently induced both gastric stasis and stomach distension, showing a strict temporal relationship with the induction of both acute and delayed pica. Radiological methods, which are non-invasive and preserve animals' welfare, are useful to study the effect of emetogenic drugs in the different gastrointestinal regions and might speed up the search for new anti-emetics.


Assuntos
Cisplatino/toxicidade , Esvaziamento Gástrico/efeitos dos fármacos , Trato Gastrointestinal/diagnóstico por imagem , Pica/fisiopatologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/toxicidade , Cisplatino/administração & dosagem , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Esvaziamento Gástrico/fisiologia , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/fisiopatologia , Injeções Intraperitoneais , Masculino , Pica/induzido quimicamente , Radiografia , Ratos , Ratos Wistar , Fatores de Tempo
20.
Life Sci ; 81(6): 468-79, 2007 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-17673260

RESUMO

Anorexia, nausea/emesis and peripheral sensorial neuropathy are frequent adverse effects associated with chemotherapy. Cannabinoids have been proposed to alleviate these effects, but their preventive properties in long-term experimental models have not been tested. This study was conducted to determine whether or not a cannabinoid agonist (WIN-55,212-2) can prevent anorexia, pica (an indirect marker of nausea in non-vomiting species, consisting of the ingestion of non-nutritive substances such as kaolin) and mechanical allodynia (a marker of peripheral neuropathy) induced by the antineoplastic drug cisplatin chronically administered. Isolated rats with free access to food and kaolin received either saline, cannabinoid vehicle, WIN-55,212-2 (1-2 mg kg(-1)), cisplatin (1-2 mg kg(-1)), or both drugs once per week for five consecutive weeks. Modifications in temperature, body weight gain, food and kaolin intake, and the threshold for mechanical allodynia were recorded. Additionally, the acute psychoactive effects of the cannabinoid (hypomotility, hypothermia, analgesia and catalepsia) were assayed by means of the cannabinoid tetrad. WIN 55,212-2 prevented the development of mechanical allodynia but not anorexia, pica and reduction in weight gain induced by chronic cisplatin. The effect of WIN 55,212-2 was evident even at a dose lacking activity in the cannabinoid tetrad. The preventive effect on cisplatin-induced mechanical allodynia exerted by the cannabinoid could be due to a neuroprotective role, as has been suggested for other conditions. The present results support the interest in the evaluation of cannabinoids for treatment of patients suffering or likely to suffer neuropathic pain.


Assuntos
Analgésicos/farmacologia , Antineoplásicos/toxicidade , Benzoxazinas/farmacologia , Cisplatino/toxicidade , Comportamento Alimentar/efeitos dos fármacos , Morfolinas/farmacologia , Naftalenos/farmacologia , Dor/tratamento farmacológico , Animais , Antidiarreicos/farmacologia , Temperatura Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Caulim/farmacologia , Masculino , Dor/psicologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/psicologia , Pica/prevenção & controle , Pica/psicologia , Ratos , Ratos Wistar
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