RESUMEN
The mechanisms of anti-inflammatory action of saturated N-acylethanolamine--N-stearoylethanolamine (NSE) were investigated on the rat model of nonspecific inflammation (thermal burns of the skin). The results showed that the NSE application in a form of aqueous suspension (10 mg/ml) on the damaged skin area during 12 days significantly accelerated the healing process of burned wounds. NSE also prevented the increase of 11-hydroxycorticosteroids content in the blood of rats with burns. There was also found a significant decrease of cytokines (IL-1beta, IL-6 and TNFalpha) levels under the NSE action. This way may be one of the mechanisms of NSE anti-inflammatory action.
Asunto(s)
11-Hidroxicorticoesteroides/sangre , Antiinflamatorios no Esteroideos/farmacología , Quemaduras/tratamiento farmacológico , Etanolaminas/farmacología , Piel/efectos de los fármacos , Ácidos Esteáricos/farmacología , Cicatrización de Heridas/efectos de los fármacos , Administración Cutánea , Animales , Quemaduras/sangre , Quemaduras/inmunología , Quemaduras/patología , Calor , Inflamación/sangre , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Interleucina-1beta/sangre , Interleucina-6/sangre , Masculino , Ratas , Ratas Wistar , Piel/inmunología , Piel/lesiones , Factor de Necrosis Tumoral alfa/sangre , Cicatrización de Heridas/fisiologíaRESUMEN
The biochemical mechanisms of anti-inflammatory effect of endocannabinoid congener N-stearoylethanolamine (NSE) was studied on the model of experimental burn in rats. The animals after the thermal burn of the skin received per os during 7 days the water suspension of NSE in a doze 10 mg/kg of body weight. In the other groups of rats the suspension was applied to the wound (the concentration of NSE was 10 mg/ml). It was shown for the first time that NSE accelerated the process of burn wound healing by the inhibition of proinflammatory cytokines (TNFalpha, IL-6) production. NSE caused the normalization of the iNOS and cNOS activity and of nitrite content in plasma, erythrocytes, liver and spleen of rats. NSE also modified the antioxidant enzymes (catalase, superoxide dismutase and glutathione peroxidase) activity and diminished the level of lipid peroxidation. The discovered anti-inflammatory NSE properties suggest the possibility of its usage for burn treatment.
Asunto(s)
Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Quemaduras/tratamiento farmacológico , Etanolaminas/uso terapéutico , Piel/efectos de los fármacos , Ácidos Esteáricos/uso terapéutico , Administración Cutánea , Administración Oral , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacología , Antioxidantes/administración & dosificación , Antioxidantes/farmacología , Quemaduras/enzimología , Quemaduras/inmunología , Quemaduras/metabolismo , Catalasa/sangre , Catalasa/metabolismo , Modelos Animales de Enfermedad , Eritrocitos/efectos de los fármacos , Eritrocitos/enzimología , Eritrocitos/metabolismo , Etanolaminas/administración & dosificación , Etanolaminas/farmacología , Glutatión Reductasa/sangre , Glutatión Reductasa/metabolismo , Interleucina-6/sangre , Interleucina-6/inmunología , Hígado/efectos de los fármacos , Hígado/enzimología , Óxido Nítrico Sintasa/metabolismo , Ratas , Piel/enzimología , Piel/lesiones , Piel/metabolismo , Bazo/efectos de los fármacos , Bazo/enzimología , Ácidos Esteáricos/administración & dosificación , Ácidos Esteáricos/farmacología , Superóxido Dismutasa/sangre , Superóxido Dismutasa/metabolismo , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/inmunología , Cicatrización de Heridas/efectos de los fármacosRESUMEN
The purpose of this study was to establish phospholipid composition of the myocardium in patients with ischemic heart disease, and to estimate possible correlation of biochemical parameters with myocardium extrasystolic activity. The patients (n = 28) including 15 patients with ischemic heart disease and 13 patients with secondary atrium septum defect (control group) were studied. During surgical intervention the right atrium myocardium bioptates were taken. Phospholipid metabolism was studied in the myocardium samples. At the eve of surgical intervention a holter monitoring was performed. Deep changes in the myocardium lipid metabolism were found, including accumulation of free and estherified cholesterol, lysophospholipids, and sphingomyeline. An increase of free cholesterol content was accompanied by accumulation of sphingomyeline. This can be an evidence of changes in the constitution of lipid rafts. Extrasystoles, particularly ventricular ones, in patients with ischemic heart disease might depend on accumulation of lysophospholipids as they took place simultaneously with it.
Asunto(s)
Complejos Cardíacos Prematuros/metabolismo , Isquemia Miocárdica/metabolismo , Miocardio/metabolismo , Fosfolípidos/metabolismo , Adulto , Complejos Cardíacos Prematuros/etiología , Complejos Cardíacos Prematuros/fisiopatología , Complejos Cardíacos Prematuros/cirugía , Electrocardiografía Ambulatoria , Femenino , Frecuencia Cardíaca/fisiología , Humanos , Masculino , Persona de Mediana Edad , Isquemia Miocárdica/complicaciones , Isquemia Miocárdica/fisiopatología , Isquemia Miocárdica/cirugíaRESUMEN
The effect of N-acylethanolamines mixture (NAE) with saturated and unsaturated acyl chains on the fatty acid composition of the rat brain under chronic morphine dependence was investigated. Long-term administration of NAE reduced morphine-induced decrease of mono- and polyunsaturated fatty acids in the rat brain crude lipid extract. Furthermore, NAE restored the acyl chain spectrum, especially the content of docosahexaenoic acid in essential phospholipids--phosphatidylcholine and phosphatidylethanolamine. Pharmacological activity of NAE depended on a dose.
Asunto(s)
Encéfalo/efectos de los fármacos , Etanolaminas/uso terapéutico , Ácidos Grasos/metabolismo , Dependencia de Morfina/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Animales , Encéfalo/metabolismo , Enfermedad Crónica , Modelos Animales de Enfermedad , Etanolaminas/administración & dosificación , Inyecciones Intraperitoneales , Masculino , Dependencia de Morfina/metabolismo , Fármacos Neuroprotectores/administración & dosificación , Ratas , Ratas WistarRESUMEN
The influence of saturated and unsaturated N-acylethanolamines (NAEs) mixture on the rat brain lipid composition under the chronic morphine dependence was studied. It was shown that the long-term administration of NAE to rats with experimental morphine dependence restored the morphine-induced alterations of the brain phospholipid composition. This effect can probably be explained by a fatty acyl transfer from NAE to sn-1 position of some brain glycerophospholipids. Another reason of NAE beneficial effect could be due to its antioxidative property, thus providing the remodelling of phospholipid composition. The restoration of the brain essential phospholipids is associated with the decline in morphine consumption in rats with experimental morphine dependence. The mechanism of this phenomenon requires further investigations.
Asunto(s)
Encéfalo/efectos de los fármacos , Etanolaminas/uso terapéutico , Dependencia de Morfina/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Fosfolípidos/metabolismo , Animales , Encéfalo/metabolismo , Enfermedad Crónica , Modelos Animales de Enfermedad , Masculino , Dependencia de Morfina/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
The influence of irradiation and NSE on the microsomal lipid composition of the rat liver and heart was studied. It was shown, that radiation treatment in a dose of 2 Gy had not a significant affect on the heart phospholipid composition, whereas in the liver the amounts of the phosphatidylethnolamine and phosphatidylinositol were increased and the amounts of the phosphatidylcholine and sphyngomieline were decreased. NSE did not impact on these characteristics. The alterations of the plasmalogen/diacyl forms ratio of the PC and PE also took place only in the liver microsome. The analysis of the fatty acids esterified to phospholipids showed similar situation: the fatty acids of the heart microsome less were changed than those of the liver microsome undergo irradiation. The amount of arachidonic acid rise after the adding of NSE to rats. Investigation of the important component of biological membranes--cholesterol and its esters also showed that the liver tissue is more vulnerable to irradiation than the heart. NSE led to insignificant increase of the not esterified cholesterol in the liver. As a result of the present work we may conclude that the liver microsome is more vulnerable than the heart under X-ray radiation and NSE has protective effect in these conditions.
Asunto(s)
Etanolaminas/farmacología , Corazón , Microsomas Hepáticos , Microsomas , Fosfolípidos/metabolismo , Protectores contra Radiación/farmacología , Ácidos Esteáricos/farmacología , Administración Oral , Animales , Etanolaminas/administración & dosificación , Corazón/efectos de los fármacos , Corazón/efectos de la radiación , Microsomas/efectos de los fármacos , Microsomas/metabolismo , Microsomas/efectos de la radiación , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Microsomas Hepáticos/efectos de la radiación , Especificidad de Órganos , Protectores contra Radiación/administración & dosificación , Ratas , Ratas Wistar , Ácidos Esteáricos/administración & dosificación , Irradiación Corporal Total , Rayos XRESUMEN
Changes of the individual phospholipid fatty acid composition under the normothermal short-time ischemia with following reperfusion were investigated. Modification of the phospholipid fatty acid (FA) composition under ischemia-reperfusion didn't bear total character and was more manifested in cardiolipin (CL) and phosphatidylethanolamine (PE). The decrease of short chain FA in these phospholipids (more than by 50%) was observed. The amount of unsaturated FA included in CL increased and whole the saturated ones decreased. This caused the rise of the unsaturation index. The selective type of the changes suggested that they had an adaptive character. The addition of the N-stearoilethanolamine (NSE) into the perfusion solution caused a normalization of saturated and unsaturated FA relative amount, as well as of omega-3 and omega-9 FA level in CL. The modification of the FA composition of phosphatidylcholine (PC), phosphatidylserine (PS) and phosphatidylinositol (PI) was also found. The quantity of arachidonic acid in PC increased by 26% and the amount of stearinic acid enhanced in PS. The labeled N-([1-(14)C]-palmitoil)-ethanolamine was found in different lipid classes of the rat organs immediately 5 min following intraperitoneal injection. Approximately 1/3 of all incorporated label accumulated in the phospholipid fraction, and more than 50% of the labels were found in CL.
Asunto(s)
Etanolaminas/farmacología , Ácidos Grasos/metabolismo , Fosfolípidos/metabolismo , Daño por Reperfusión/metabolismo , Ácidos Esteáricos/farmacología , Animales , Masculino , Fosfolípidos/química , Ratas , Ratas WistarRESUMEN
The effect N-stearoilethanolamines on lipide classes and their fatty acid composition was studied in the isolated rat heart under ischemia--reperfusion. It was shown that the amount of cholesterol esters increased at ischemia--reperfusion by 4.6 fold. The addition of 10(-7) M, 10(-6) M and 10(-5) M of N-stearoilethanolamines into perfused solution prevented these negative consequences of the myocardium ischemic injury. The addition of N-stearoilethanolamines decreased the quantity oleinic (18:1 omega 9) and free n-6 fatty acids. N-stearoilethanolamine lowered the amount of short chain saturated fatty acids and also polyunsaturated n-6 fatty acids in cholesterol esters. As well the lipide composition of perfused solutions was also investigated.
Asunto(s)
Colesterol/química , Etanolaminas/farmacología , Ácidos Grasos Insaturados/química , Ácidos Grasos/química , Miocardio/metabolismo , Daño por Reperfusión/metabolismo , Ácidos Esteáricos/farmacología , Animales , Técnicas In Vitro , Masculino , Ratas , Ratas WistarRESUMEN
The possibility of NAE to take part in the regulation of the function of adrenal glands was studied. It was shown that two times NAE (18:0) injection in a dose 5 mg/kg of weight increased the content of 11-hydroxysteroids in blood of intact male rats. NAE caused the raise of the blood hormone content in 4 fold under the immobilization stress. It is apparent that augment of stress response under the influence of NAE in vivo is explained by the activation of hypophysis-adrenal cortex system. In vitro NAE lowered steroidogenesis by near 40%. One can suggest that this decrease is caused by membranotropic properties of NAE.
Asunto(s)
Corteza Suprarrenal/efectos de los fármacos , Etanolaminas/farmacología , Corteza Suprarrenal/fisiología , Animales , Inmovilización , Masculino , Ratas , Ratas WistarRESUMEN
The erythrocyte ghosts fatty acid composition of 27 patients with coronary artery disease (CAD) and 6 healthy people were investigated. Patients suffering from CAD were divided in two groups. The first group was matched by 18 patients with CAD and essential hypertension (EH) and 9 patients with CAD without EH. Significant decrease of the levels of some saturated fatty acids such as palmitic, stearic and begenic acids in the erythrocyte ghosts of the patients with CAD without EH was established among the major changes of the erythrocyte ghosts fatty acid composition. At the same time the amount, of arachidonic acid increased by 74% and docosahexaenoic acid--by 5.7 times. The content of miristic, palmitic and stearic acids was also diminished in patients with CAD and EH. The percent of arachidonic acid was elevated by 51% and docosatrienic acid--by 94%. It is notable that the quantity of docosahexaenoic acid did not change markedly if copmare to healthy people but was fallen for 5 times if compare to patients with CAD without EH. It was suggested that the lack of adaptive changes in erythrocyte ghosts omega-3 fatty acids of patients with CAD and EH was an important factor which could rise the risk of heart attack development.
Asunto(s)
Membrana Eritrocítica/metabolismo , Ácidos Grasos/metabolismo , Isquemia Miocárdica/metabolismo , Estudios de Casos y Controles , Ácidos Grasos/clasificación , Humanos , Hipertensión/complicaciones , Isquemia Miocárdica/complicacionesRESUMEN
The heart contractility and changes of lipid composition of isolated rat heart (n = 26) under total ischemia and ischemia-reperfusion was studied. The effect of N-stearoyl-ethanolamine under these conditions was investigated. N-stearoyl-ethanolamine leads to remodelling of fatty acyl chain composition of myocardial phospholipids: to drastic fall of polyunsaturated fatty acyl chains (18:2w6, 20:3w6, 20:4w6, 22:5w3, 22:5w6, 22:6w3 and 22:6w6) and enhancement of 18:0. This can be caused by N-stearoyl-ethanolamine-induced suppression of polyunsaturated fatty acids synthesis. Naturally occurring minor lipids--N-acyl phosphatidylethanolamine and its derivative N-acylethanolamine were detected in isolated rat heart under ischemia-reperfusion. It is notable that approximately 12% of total N-acylethanolamines were composed by anandamide. Treatment of N-acyl phosphatidylethanolamine by phospholipase D with subsequent fatty acyl chain analysis demonstrates that fatty acid composition of both N-acyl chains of N-acyl phosphatidylethanolamine and free N-acylethanolamine are similar and their main fatty acyl chains are 16:0, 18:0 and 20:4w6. It was shown that exogenous N-stearoyl-ethanolamine did not alter the levels of endogenous N-acyl phosphatidylethanolamine and N-acylethanolamine, but caused the decrease of lyso-phosphatidylcholine and phosphatidylglycerol levels. The rate of heart contractility and heart relaxation was found to increase during the early period of reperfusion. N-stearoyl-ethanolamine prevents this alteration and exerts a negative inotropic effect. It is concluded that membrane protective properties of N-stearoyl-ethanolamine at least partly depend on its ability to inhibit decrease amount of arachidonic and docosahexaenoic acids, to modulate the fatty acyl chains of cardiac phospholipids and to decrease the level of lyso-phosphatidylcholine.
Asunto(s)
Etanolaminas/metabolismo , Lípidos/fisiología , Contracción Miocárdica , Daño por Reperfusión Miocárdica/metabolismo , Animales , Etanolaminas/química , Técnicas In Vitro , Masculino , Sondas Moleculares , Fosfolipasa D/química , Ratas , Ratas WistarRESUMEN
N-acyl-ethanolamines (NAE) belong to the new class of naturally occurring biologically active regulators. Anandamide--a well known representative of NAEs--is an agonist of central (CB1) and peripheral (CB2) cannabinoid receptors. Adrenal cortex contains the CB2 receptor. The aim of present work is to investigate the influence of saturated and polyunsaturated NAEs on the corticosteroid synthesis in adrenal gland in vitro. It was shown that the rat adrenal gland is the main target of N-([1-14C]palmitoyl)ethanolamine incorporation. Saturated NAE enhanced the incorporation of [3H]-cholesterol into the aldosterone by 25% (p < 0.06) and corticosterone by 17% (p < 0.05) of rat adrenal slices in vitro. Mixture of polyunsaturated NAEs containing mainly 18:1w9, 18:2w6, 18:3w3, 20:1w9, 22:1w9 increased the labeling of aldosterone by 70% (p < 0.05) and corticosterone by 20% (p < 0.05). Thus, the saturated NAEs as well as polyunsaturated analogs, act by the similar manner on the corticosteroid synthesis. The fact that saturated NAEs possess poor affinity to CB receptors provides us opportunity to suggest the non-receptor mechanism of NAEs adrenotrophic action. Further we used the purified bovine serum albumin to test the binding kinetic of N-([I14C]palmitoyl)ethanolamine with its hydrophobic domains. It was found that NAEs have high affinity to hydrophobic domains of protein with K = 2.5 x 10(8) M-1. This finding could support the idea of the existence of putative allosteric modulation of regulatory protein function. It was concluded that NAEs exert a stimulatory effect on the corticosteroid synthesis in rat adrenal gland in vitro and this action do not mediated trough cannabinoid receptor.
Asunto(s)
Glándulas Suprarrenales/efectos de los fármacos , Etanolaminas/farmacología , Receptor Cannabinoide CB2 , Glándulas Suprarrenales/metabolismo , Animales , Bovinos , Colesterol/metabolismo , Etanolaminas/química , Femenino , Cinética , Ratas , Receptores de Cannabinoides , Receptores de Droga/agonistasRESUMEN
The possibility of NAE to take part in the regulation of the function of adrenal glands was studied. It was shown that two times NAE (18:0) injection in a dose 5 mg/kg of weight increased the content of 11-hydroxysteroids in blood of intact male rats. NAE caused the raise of the blood hormone content by 4 times under the immobilization stress. It is apparent that augment of stress response under the influence of NAE in vivo is explained by the activation of hypophysis-adrenal cortex system. In vitro NAE lowered steroidogenesis by near 40%. One can suggest that this decrease is caused by membranotropic properties of NAE.
Asunto(s)
Corteza Suprarrenal/efectos de los fármacos , Corteza Suprarrenal/fisiología , Etanolaminas/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Etanolaminas/administración & dosificación , Hidroxiesteroides/sangre , Inmovilización , Masculino , Ratas , Estrés Fisiológico/sangreRESUMEN
Data concerning the synthesis of bioactive lipid compound N-([1-14C]-palmitoyl)ethanolamine labeled by 14C fatty acid are reported. The method is based on the ability of ethanolamine and fatty acid to the direct chemical condensation at 180 degrees C with yielding of N-acylethanolamine. The purification of the end product by the double crystallization in ethanol allows to obtain chromatographically pure substance. The presented method of the labeled N-([1-14C]-palmitoyl)ethanolamine synthesis is simple and in extensive that's why it might be used in the area of biologically active compounds investigation.
Asunto(s)
Fosfatidiletanolaminas/síntesis química , Radioisótopos de Carbono , Cromatografía de Gases , Fosfatidiletanolaminas/química , Fosfatidiletanolaminas/aislamiento & purificaciónRESUMEN
N-([1-14C]-palmitoyl)-ethanolamine distribution was studied in the rat tissues. The following sequence of the label inclusion into tissues by the way of decreasing the radio activity: adrenal >> diaphragm > spleen > kidney > testis > lung > liver > heart > brain > plasma > erythrocytes was obtained.
Asunto(s)
Ácidos Palmíticos/farmacocinética , Amidas , Animales , Radioisótopos de Carbono , Endocannabinoides , Etanolaminas , Masculino , Ratas , Distribución TisularRESUMEN
The brain phospholipid content was studied in rats with morphine physical dependence. It was found that level of total lipids, total phospholipids and cholesterol was diminished. The significant decrease of absolute amounts of phosphotidyl serine, phosphotidyl inositol, sphingomyelin and phosphatidyl choline was shown. At the same time the percent relation of individual phospholipids did not change. As the exclusion, the quantity of phosphatidyl ethanolamine plasmalogen lowered in rats with morphine dependence. The percent content of fatty acids 16:0, 18:1 omega 9, 20:1 omega 11, 20:4 omega 6 and 22:5 omega 3 was found to be reduced. At the same time the percent amount of i18:0 and 20:0 was shown to increase. As a result the unsaturation index dramatically diminished. It was also shown that under morphine physical dependence the acyl residues of phosphatidyl choline and phosphatidyl ethanolamine changed. It was concluded that lipids play significant role in the development of morphine physical dependence.