Effects of vincristine and monosodium glutamate on gastrointestinal motility and visceral sensitivity.

BACKGROUND: Chemotherapy-induced adverse effects are an unresolved nightmare. In preclinical studies in rats, the food additive monosodium glutamate (MSG) improved some of the side effects caused by cisplatin, but its effects in other models of chemotherapy-treated animals are not well known. The aim of this study was to test if MSG may improve some of the adverse effects induced by vincristine in rats. METHODS: Young male Wistar rats were exposed or not to MSG (4 g L-1 ) in drinking water from week 0 till 1 week after treatment (week 3). Rats received two cycles of five daily intraperitoneal (ip) injections (Monday to Friday, weeks 1 and 2) of either saline (2 mL kg-1 ) or vincristine (0.1 mg kg-1 ). Gastrointestinal motility was measured in vivo by radiological methods after the first and tenth ip administrations. On week 3, the threshold for mechanical somatic and colorectal sensitivity was recorded using Von Frey filaments applied to the paws and an intracolonic balloon, respectively. Finally, samples of the terminal ileum and distal colon were histologically evaluated in sections. KEY RESULTS: Vincristine reduced body weight gain, food intake, and upper gastrointestinal transit, caused somatic (but not visceral) hypersensitivity and increased the thickness of the submucosal and muscle layers of the small intestine. In vincristine-treated animals, MSG partially prevented gastrointestinal dysmotility and reduced visceral sensitivity but did not improve structural alterations of the small intestine. CONCLUSIONS & INFERENCES: MSG could be used as an adjuvant to conventional treatments to improve some gastrointestinal dysfunctions caused by chemotherapy.

Cisplatin cycles treatment sustains cardiovascular and renal damage involving TLR4 and NLRP3 pathways.

Cisplatin is clinically proven to combat different cancers, including sarcomas, soft tissue cancers, bones, muscles, and blood. However, renal and cardiovascular toxicities are important limitations in cisplatin therapeutical use. Immunoinflammation could be key factor in cisplatin-induced toxicity. The aim of the present study was to evaluate the activation of the inflammatory TLR4/NLRP3 pathway as a common mechanism for cardiovascular and renal cisplatin's cycles treatment toxicity. Adult male Wistar rats were treated with saline, cisplatin 2 mg/kg or cisplatin 3 mg/kg (intraperitoneally once a week, for five experimental weeks). After treatments, plasma, cardiac, vascular, and renal tissues were collected. Plasma malondialdehyde (MDA) and inflammatory cytokines were determined. TLR4, MyD88, NF-κß p65, NLRP3, and procaspase-1 tissue expressions were also analyzed. Cisplatin treatment induced a dose-dependent increase in plasma MDA and IL-18. In cardiovascular system, an increase in NLRP3 and in cleaved caspase-1 were observed in cardiac tissue and a moderate increase in TLR4, MyD88 appeared in mesenteric artery. In kidney, a significant dose-dependent increase in TLR4, MyD88 and NLRP3 and cleaved caspase 1 expressions were observed after cisplatin treatments. In conclusion, cisplatin cycles provoke a low grade pro-inflammatory systemic state. Kidney was more sensitive than cardiovascular tissues to this pro-inflammatory state. TLR4 and NLRP3 are key pathways involved in renal tissue damage, NLRP3 is the main pathway involved in cardiac toxicity and TLR4 pathway in resistance vessel toxicity.

Cardiovascular Toxicity Induced by Chronic Vincristine Treatment.

Vincristine is an effective anticancer agent for treating leukemias, lymphomas, and other solid tumors. Vincristine's better-known severe side effects include bone marrow depression, hyponatremia, peripheral neuropathy, and gastrointestinal distress. In recent years, cardiovascular damage also has been described during vincristine treatments. However, the vascular toxicity induced by vincristine is little studied. The aim of the present is to evaluate whether these alterations remain after the suspension of chemotherapy treatment (sequelae) and the possible mechanisms involved in this vascular damage. Adult male Wistar rats were used. The animals were divided into four treatment groups: two groups of saline (0.9% NaCl; saline, sequelae saline) and two groups of vincristine (100 µg/kg; vincristine, sequelae vincristine). Saline or vincristine was administered intraperitoneally in two cycles of 5 days each, leaving a rest period between cycles of 2 days. The final cumulative vincristine dose administered was 1 mg/kg. Sequelae groups correspond to 2 weeks after stopping treatment with the antitumor agent. At the end of the different experimental protocols, cardiac and vascular functions were analyzed. Alterations in the expression of different proteins in the cardiovascular tissues were also investigated. Chronic treatment with vincristine did not produce significant changes in basal cardiac function but provoked significant endothelial dysfunction in the aorta and a significant decrease in the mesenteric contractile function. These cardiovascular functional alterations disappeared 2 weeks after the suspension of chemotherapy treatment. Vincristine treatment caused a significant increase in the expression of tumor necrosis factor-alpha (TNFα), endothelial and inducible nitric oxide synthases (eNOS and iNOS), and connexin 43 in cardiac tissue. In the aorta, the chronic treatment with vincristine caused a slight non-significant increase in TNFα expression, a significant increase in eNOS and iNOS, and a significant decrease in connexin 43. After 2 weeks of vincristine treatment (sequelae group), the expression of TNFα increased and eNOS and iNOS expressions disappeared, but a significant decrease in the expression of connexin 43 was still observed in the aorta. In mesenteric arteries, similar data to those found in the aorta were observed. In conclusion, chronic treatment with vincristine causes functional alterations in the vascular function of both conductance and resistance vessels and changes in the expressions of TNFα, eNOS, iNOS, and connexin 43 in cardiovascular tissues, implicating direct toxicity during its treatment. These functional alterations are transitory and disappear after the suspension of its treatment.

Egg white hydrolysates improve vascular damage in obese Zucker rats by its antioxidant properties.

Metabolic Syndrome (MS) is related to increased risk of early death due to cardiovascular complications, among others. Dietary intervention has been suggested as the safest and most cost-effective alternative for treatment of those alterations in patients with MS. The aim of this study was to investigate the effects of different egg white hydrolysates (HEW1 and HEW2) in obese Zucker rats, focus on the development of cardiovascular complications. Blood pressure, heart rate, basal cardiac function and vascular reactivity in aorta and mesenteric resistance arteries were evaluated. Reactive oxygen species production by dihydroethidium-emitted fluorescence, NOX-1 mRNA levels by qRT-PCR, angiotensin-converting enzyme activity by fluorimetry and kidney histopathology were also analysed. Both hydrolysates improve the endothelial dysfunction occurring in resistance arteries. Additionally, HEW2 reduced vascular oxidative stress. PRACTICAL APPLICATIONS: Egg white is a good source of bioactive peptides, some of them with high antioxidant activity. They may be used as functional foods ingredients and could serve as an alternative therapeutic option to decrease some Metabolic Syndrome-related complications. This study suggests that these hydrolysates could be an interesting non-pharmacological tool to control cardiovascular complications related to Metabolic Syndrome.

Changes in the diet composition of fatty acids and fiber affect the lower gastrointestinal motility but have no impact on cardiovascular parameters: In vivo and in vitro studies.

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.

Characterization of Cardiovascular Alterations Induced by Different Chronic Cisplatin Treatments.

In the last years, many clinical studies have revealed that some cisplatin-treated cancer survivors have a significantly increased risk of cardiovascular events, being cisplatin-induced cardiovascular toxicity an increasing concern. The aim of the present work was to evaluate the cardiovascular alterations induced by different chronic cisplatin treatments, and to identify some of the mechanisms involved. Direct blood pressure, basal cardiac (left ventricle and coronary arteries) and vascular (aortic and mesenteric) functions were evaluated in chronic (5 weeks) saline- or cisplatin-treated male Wistar rats. Three different doses of cisplatin were tested (1, 2, and 3 mg/kg/week). Alterations in cardiac and vascular tissues were also investigated by immunohistochemistry, Western Blot, and or quantitative RT-PCR analysis. Cisplatin treatment provoked a significant modification of arterial blood pressure, heart rate, and basal cardiac function at the maximum dose tested. However, vascular endothelial dysfunction occurred at lower doses. The expression of collagen fibers and conexin-43 were increased in cardiac tissue in cisplatin-treated rats with doses of 2 and 3 mg/kg/week. The expression of endothelial nitric oxide synthase was also modified in cardiac and vascular tissues after cisplatin treatment. In conclusion, chronic cisplatin treatment provokes cardiac and vascular toxicity in a dose-dependent manner. Besides, vascular endothelial dysfunction occurs at lower doses than cardiac and systemic cardiovascular toxicity. Moreover, some structural changes in cardiac and vascular tissues are also patent even before any systemic cardiovascular alterations.

Characterization of cannabinoid-induced relief of neuropathic pain in rat models of type 1 and type 2 diabetes.

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.

[Resveratrol: a neuroprotective polyphenol in the Mediterranean diet]. / Resveratrol: un polifenol neuroprotector de la dieta mediterranea.

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.

Resveratrol: un polifenol neuroprotector de la dieta mediterránea / Resveratrol: a neuroprotective polyphenol in the Mediterranean diet

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)

Cannabinoid/agonist WIN 55,212-2 reduces cardiac ischaemia­reperfusion injury in Zucker diabetic fatty rats: role of CB2 receptors and iNOS/eNOS.

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.

Cytochrome P450 pathway contributes to methanandamide-induced vasorelaxation in rat aorta.

PURPOSE: The generation of hyperpolarising vasorelaxant endothelial cytochrome P450 epoxygenase (CYP)-derived metabolites of arachidonic may provide beneficial effects for the treatment of cardiovascular diseases in which the bioavailability of NO is impaired. The cannabinoid methanandamide has vasodilatory properties linked to hyperpolarisation. The aim of the present work was to investigate the vasorelaxant effects of methanandamide in rat aorta, focusing on the role of cytochrome P450 pathway. METHODS: Changes in isometric tension in response to a cumulative concentration-response curve of methanandamide (1 nM-100 µM) were recorded in aortic rings from male Wistar rats. The involvement of cannabinoid receptors, endothelial nitric oxide (NO)-, prostacyclin- and some hyperpolarising-mediated pathways were investigated. The activation of large-conductance Ca(2+)-activated K(+) (BKCa) channels have also been evaluated. RESULTS: Methanandamide provoked an endothelium-dependent vasorelaxation in rat aorta, reaching a maximal effect (Rmax) of 67% ± 2.6%. This vasorelaxation was clearly inhibited by the combination of CB(1) and CB(2) cannabinoid antagonists (Rmax: 21.6% ± 1.3%) and by the combination of guanylate cyclase and CYP inhibitors (Rmax: 16.7% ± 1.1%). The blockade induced separately by guanylate cyclase (31.3% ± 2.8%) or CYP (36.3% ± 6.6%) inhibitors on methanandamide vasorelaxation was not significantly modified by either CB(1) or CB(2) inhibition. BKCa channels inhibition caused a partial and significant inhibition of the methanandamide vasorelaxation (Rmax: 39.9% ± 3.3%). CONCLUSIONS: Methanandamide endothelium-dependent vasorelaxation is mediated by CB(1) and CB(2) cannabinoid receptors. The NO- and CYP-mediated pathways contribute in a concurrent manner in this vascular effect. Stimulation of both cannabinoid receptor subtypes is indistinctly linked to NO or CYP routes to cause vasorelaxation.

Vascular toxicity of chemotherapeutic agents.

Cancer chemotherapy is not free of undesirable side effects. With respect to the cardiovascular system, cardiotoxicity is a well-described and potentially lethal side effect of certain chemotherapeutic agents, such as anthracyclines. However, in the last few years, several clinical studies have taken into account the fact that some non-anthracycline chemotherapy treated-patients also have a significantly increased risk of cardiovascular events. The exact mechanism of this toxicity is not known, and several possibilities, including vascular autonomic neuropathy and vascular damage, have been proposed. The aim of the present review was to collate information on the clinical and experimental evidence regarding vascular toxicity for each of the different groups of chemotherapeutic agents. The mechanisms proposed to underlie this toxicity are also discussed.

Vasorelaxation caused by cannabinoids: mechanisms in different vascular beds.

Cannabinoids (natural, endogenous and synthetic compounds) produce vasorelaxation in resistance and conduit arteries. Several putative mechanisms have been proposed to explain this effect of cannabinoids. The aim of the present review is to discuss the different mechanisms involved in the vasorelaxant effect of endogenous and synthetic cannabinoids in resistance and conduit arteries. Research on the vascular effects of cannabinoids suggests that the magnitude of the vasorelaxation and the mechanisms involved are not identical in all vascular beds with one or two mechanisms predominating. Either extracellular or intracellular mechanisms are involved. With regard to the former, the stimulation of cannabinoid CB1, CB2 or nonCB1/nonCB2 cannabinoid receptors and the stimulation of vanilloid receptors, transient potential vanilloid receptors, on perivascular nerve endings with the subsequent release of the vasodilator neurotransmitter calcitonin gene-related peptide have been described. With regard to the latter, the main mechanisms implicated include nitric oxide release, metabolism to vasoactive arachidonic metabolites or prostanoid analogues, or endothelium derived hyperpolarising factor release. The knowledge of these mechanisms is crucial to identify new therapeutic targets and to understand the consequences in different vascular beds.

Anandamide vehicles: a comparative study.

Among the studies that investigate the vasorelaxation induced by anandamide, one of the most frequent differences is the use of distinct solvents that could modify vascular function and explain the controversial results described. The aims of this study were: to evaluate the influence of different cannabinoid vehicles in vascular function of rat aorta, and to compare the vasorelaxation induced by anandamide dissolved in different vehicles. Vehicles were: ethanol (70%), Tween 80/ethanol (2:1 and 1:1), 1:1:18 (Tween 80/ethanol/saline) and dimethylsulphoxide (DMSO) 0.5%. All the vehicles tested, except DMSO 0.5%, modified the vascular and/or the endothelial function in rat aorta rings. Anandamide caused a time- and concentration-dependent vasorelaxation in all the experimental groups except in ethanol group, but the mechanisms involved in its vasorelaxation appear to be different depending on the vehicle used. The results obtained with vehicles containing Tween 80 suggest a non-endothelial component in the vasorelaxation caused by anandamide, while those obtained with DMSO at 0.5% suggest an endothelial component in this vasorelaxation.