Control de las enfermedades metabólicas en vacas lecheras

Presentación del tema: "Control de las enfermedades metabólicas en vacas lecheras"— Transcripción de la presentación:

1 Control de las enfermedades metabólicas en vacas lecheras
Roberto Farina DVM – Fatro Group

2 Alta incidencia de enfermedades metabólicas
El control de las enfermedades metabólicas es de crucial importancia en los rodeos lecheros modernos Alimentación y Manejo intensivo Susceptibilidad en las vacas de alta producción Metabolic disorders are also more prevalent with an inadequate transition program. These are costly in terms of lost milk production, vet and drugs and discarded milk. Estimates from the U.S. place the economic loss from milk fever at $334, $285 for retained placentas and $145 for ketosis (U.S. dollars). Occurrence of one metabolic disease also predisposes cows to other metabolic diseases. A U.S. study of 31 dairies during the first 30 days after calving showed significant relationships between various metabolic diseases. Cows with milk fever were 4 times more prone to retained placentas and 24 times more prone to ketosis. Cows with retained placentas were 16 times more prone to ketosis and six times more prone to metritis. Cows with displaced abomasums were 54 times more likely to develop ketosis. Alta incidencia de enfermedades metabólicas

3 Metabolismo Son todos los cambios bioquímicos y físicos que se producen en el organismo que posibilitan su crecimiento y funcionalidad

4 Regulación del metabolismo
La coordinación del metabolismo de los tejidos del organismo involucra 2 tipos de regulación Homeostasis Homeorhesis Chreods and contingency physics and mathematics – chaos theory. biology – contingency; the irreversible character of natural selection. (Gleick, 1987, Gould, 1991), Mokyr (1991) biology - necessary path (or chreod); Conrad Hall Waddington ( Principles of Embryology (Waddington, 1956, p. 412) “developmental reactions...are in general canalized. That is to say, they are adjusted so as to bring about one end result regardless of minor variations in conditions during the course of the reaction.” (Waddingon, 1941) homeostasis vs. homeorhesis “The stabilization of a progressive system acts to ensure that the system goes on altering in the same sort of way that it has been altering in the past. Whereas the process of keeping something at a stable, or stationary, value is called homeostasis, ensuring the continuation of a given type of change is called homeorhesis, a word which means preserving a flow. A phrase used to describe such systems, is to say that the pathway of change is canalized. For the pathway itself one can use the name chreod, a word derived from Greek, which means ‘necessary path’. (Waddington, 1977)

5 Homeostasis – Resistencia al Cambio
Mantenimiento del equilibrio fisiológico Este control trabaja para mantener constantes las condiciones dentro del ambiente interno Es la propiedad de regresar un sistema al estado en que se encontraba antes de ser alterado

6 Homeorhesis – Mantenimiento del Flujo
Cambios coordinados en el metabolismo para adaptarse a un nuevo estado fisiológico The idea was proposed over 50 years ago by embryologist and geneticist, Conrad Hall Waddington ( ). The idea of necessity path was used by Waddingon to describe the development process of different cells of biological organisms but in later works he has extended this idea to socio-economic processes. Waddington see the development of any single cell of biological organism as its movement in the so-called epigenetic landscape. He portrayed the process in his Principles of Embryology (Waddington, 1956, p. 412) by landscape of valleys representing different fates the cell might roll into (see Fig. 1). At the beginning of its journey, development is plastic, and a cell can become many fates. However, as development proceeds, certain decisions cannot be reversed. Implicit in this model is the notion of canalization (and this idea is presented in his earlier work, namely in (Waddingon, 1941), where he writes that “developmental reactions...are in general canalized. That is to say, they are adjusted so as to bring about one end result regardless of minor variations in conditions during the course of the reaction.” To Waddington canalization is not unlike the current notion of "developmental constraints". Very frequently general vision of development of dynamical system is based on cybernetic concept of negative feedback leading to the stable equilibrium. This regulatory process of stabilizing the development and tendency to return to initial equilibrium is called homeostasis. There is enormous number of examples of homeostatic systems in biological and socioeconomic spheres of life. But developing systems are changing all the time, moving along some defined time trajectory, from an initial stage, such as a fertilized egg, through various larval stages to adulthood, and finally to senescence. The regulation that occurs in such systems is a regulation not back to an initial stable equilibrium, as in homeostasis, but to some future Un ejemplo de esto es el “período de transición” en la vaca lechera, donde unaserie de coordinados cambios ocurren para llevar adelante una lactancia exitosa

7 El período de transición
3 semanas antes y 3 semanas después del parto (Grummer 1995) Preñada Seca Vacía Lactando Cambio extremo La mayoría de las enfermedades infecciosas o metabólicas en la vaca lechera ocurren durante o inmediatamente después de este período

8 Balance Energético Negativo
4 dias postparto Adapted from Bell by Drackley 1999 Después del parto los requerimientos extra de energía para la lactación no son abastecidos por el alimento

9 Consumo de Materia Seca alrededor del parto
Parturition 5 10 15 20 25 30 35 -20 -18 -16 -14 -12 -10 -8 -6 -4 -2 2 4 6 day relative to calving lb of dry matter/day Bertice 1992

10 Demanda de glucosa vs aporte de glucosa durante el periparto
Overton 1998 & Douglas 1998 Después del parto la provisión de glucosa es menor que la demanda en alrededor de 500 gr/día

11 Centralidad de el Hígado
Gluconeogenesis Glycogenesis Glycogenolysis Synthesis of Lipoprotein Cholesterol Phospholipids Deamination of Aminoacids Transamination reactions Synthesis of Urea Synthesis of Amino Acids Synthesis of Albumin Synthesis of Clotting Factors Fibrinolytic Factors Oxidation of Fatty Acids Ketogenesis Bile production Metabolism of Hormones Vitamins Detoxification of Xenobiotics Detoxification of Drugs Detoxification of end-metabolism products Centralidad de el Hígado El hígado es el cruce de rutas del metabolismo Su rápida adaptación para soportar la lactancia es central para una transición sin contratiempos Liver plays critical roles in synthesizing molecules that are utilized elsewhere to support homeostasis, in converting molecules of one type to another, and in regulating energy balances Dairy cows in early lactation are especially dependent on hepatic gluconeogenesis

12 Adaptación hepática para la lactancia
Prepartum Postpartum Incremento Flujo hepático de sangre 1140 l/h 2099 l/h + 84% Consumo de Materia Seca 9.8 kg/d 14.1 kg/d + 44 % Consumo hepático de Oxígeno 1619 mmol/h 3159 mmol/h + 95 % Actividad metabólica del hígado 4.4 mmol O2/g 8.6 mmol O2/g X 2

13 Los grandes desafíos de el hígado durante el período de transición
Altos requerimientos de energía Extensa movilización de ácidos grasos Dramático incremento de la actividad metabólica Hígado graso Intoxicación amoniacal Estrés oxidativo

14 Medidas efectivas para controlar enfermedades metabólicas en vacas lecheras
L-Carnitina y sus múltiples ventajas para tratar desórdenes metabólicos Proliferadotes peroxisomales Vías para detoxificar amoníaco Control del estrés oxidativo

15 Quemando grasa hepática
Hígado Graso Quemando grasa hepática

16 Síndrome de movilización de grasas
Vacuoles in hepatocytes of a liver showing steatosis Las vacas movilizan ácidos grasos desde el tejido adiposo para cubrir el déficit de energía TG´s se acumulan el el hígado en la mayoría e las vacas en las primeras semanas post-parto. El Hígado graso es común en la mayoría de las vacas (más del 50% de vacas lecheras de alta producción.) Dairy cows rely on glucose for energy. Glucose is produced in the liver from propionic acid, a product of rumen digestion. When DMI is reduced or energy requirements are greater than energy intake, glucose synthesis is inadequate due to insufficient amounts of propionic acid. Alternate sources of energy must be found and body fat stores begin to be broken down. There is also a normal breakdown of body fat around calving time because of the hormonal changes associated with calving. This happens in varying degrees with all transistion cows. Stress situations also increase mobilization of body fat stores.The breakdown of body fat stores causes the release of nonesterified fatty acids(NEFA). Low energy levels mean the NEFAs are not completely oxidized in the liver. This results in the production of ketone bodies, which cause ketosis, and the increased accumulation of triglycerides in the liver, resulting in fatty liver. Thin cows have greater mobilization of body fat due to decreased insulin levels and a greater conversion of the resulting NEFAs to triglycerides and ketones. The liver is not a storage site for body fat but becomes fat as the cow is losing weight. As the amount of fat in the liver increases, liver function is adversely affected. It appears that ketosis occurs after a cow develops a fatty liver.

17 Metabolismo lipídico durante el período de transición
Peroxisomas Tejido adiposo Insulin TG Hígado Graso + Stress Hormones NEFA NEFA Hígado TG CPT Mitocondria BETA-OXIDACIÓN Calving is a critical time in the cow’s productive life and management though this period can significantly impact performance in the upcoming lactation. During the transition period (3 weeks prior to 3 weeks after calving), the dairy cow undergoes many changes. These include both physiological (hormonal, nutritional) and environmental (housing, social group) changes. Management of the cow throughout this period should target high feed intake, cow comfort and animal health for optimal lactation performance. Cows mobilize fatty acids from adipose tissue to compensate for energy deficit NEFA are transported by serum albumins and taken up by the liver NEFA - Non Etherified Fatty Acids NEFA are used for energy production formation of ketone bodies converted into triacylglycerols (TAG) and then secreted with very low density lipoproteins (VLDL) When the formation of TAG is in excess, TAG accumulate, resulting in the condition known as fatty liver VLDL CO2 Cuerpos cetónicos

18 Concentración sérica de NEFA alrededor del parto
NEFA mM/L Weeks relative to calving

19 Concentración sérica de NEFA alrededor del parto
Underwood 1998 NEFA concentration mEq/L Days from parturition

20 Day relative to calving
Cambios en la concentración de TG`s en hígado y su relación con el parto Liver TG - % DM basis hepatic steatosis has largely developed by the day after parturition The large increase in TG levels at calving relative to the pretreatment values demonstrates that fat infiltration of the liver occurs before the high energy demand of lactation even begins. The liver TG levels increase even more during the early weeks of lactation, indicating that the cow is mobilizing even more body fat in support of milk production. Day relative to calving Vazquez-Anon 1994

21 Acumulación lipídica en hígado
Deterioro de la función hepática Síntesis y biotransformación de metabolitos Detoxificación y excreción de deshechos tóxicos y xenobióticos Detrimento en la salud, bienestar, productividad y reproducción en la vacas lecheras

22 Acumulación lipídica en hígado
Disminución del consumo Baja performance reproductiva Disminución en la producción de leche Disminución de la inmunidad

23 Hígado Graso Está asociado con un incremento de las enfermedades metabólicas e infecciosas: Cetosis Desplazamiento el abomaso Fiebre de leche Síndrome de vaca caída Infertilidad Mastitis Metritis

24 Efectos de los NEFA en la secreción de IgM por los PBMC
Effects of NEFA on IgM secretion in peripheral blood mononuclear cells stimulated with pokeweed mitogen. PBMC = peripheral blood mononuclear cells. N. Lacetera 2004

25 Efectos de los NEFA en la secreción de Interferón-γ por los PBMC
N. Lacetera 2004

26 Incidencia de Mastitis (30 días) (2 wk after vs. 2 wk before calving)
Altos NEFA e Hígado graso están relacionados con un deterioro del sistema inmune Incidencia de Mastitis (30 días) Hepatic fat increment (2 wk after vs. 2 wk before calving) Curtis 1989

27 Control of hepatic lipidosis
Estimulando la β-oxidación peroxisomal Peroxisomas Tejido adiposo Reduciendo la movilización de NEFA TG Hígado Graso NEFA NEFA Liver TG Mitocondria Estimulando la síntesis de VLDL CPT β-oxidación VLDL Estimulando la β-oxidación mitocondrial CO2 Ketone Bodies

28 Activación de la β-oxidación mitocondrial
Baja tasa de síntesis y secreción de VLDL en el hígado de rumiantes Oxidación es el medio mas importante para disminuir el exceso de ácidos grasos del hígado Ruminants may have evolved without mechanisms necessary for high rates of VLDL secretion because of limited precursor for TG synthesis. The exception to this hypothesis may have been near calving; however, without the burden of copious milk secretion following calving, liver TG stores of predomesticated cattle could have been depleted in a relatively short time. L-Carnitina

29 La membrana interna de la mitocondria es impermeable a los ácidos grasos
Carnitine La Carnitina transporta los FA al interior de la mitocondria donde son quemados para producir energía (β-oxidación)

30 The Carnitine Shuffle Acyl CoA synthetase
Carnitine-palmitoyl transferase (CPT-I and CPT-II) Carnitine acylcarnitine translocase (CAT)

31 Activación de la β-oxidación peroxisomal
Camino alternativo para oxidar FA cuando ocurre la extensa movilización de NEFA Es inducida por la grasa de la dieta, inanición, diabetes y algunos compuestos An alternate pathway for hepatic oxidation of NEFA is present in peroxisomes, which are subcellular organelles present in most organs of the body. The oxidative pathway in peroxisomes is similar to that in mitochondria, with key exceptions. First, the initial oxidation step is catalyzed by an oxidase (acyl-CoA oxidase), which results in production of hydrogen peroxide rather than reduced NAD. This difference results in capture of less energy in reduced cofactors and more heat release during peroxisomal β-oxidation than in mitochondrial β-oxidation. Second, peroxisomes do not contain a respiratory chain linked to ATP formation. Consequently, peroxisomal β-oxidation is not subject to control by energy demands of the cell. These characteristics serve to make peroxisomal β-oxidation well suited to partially oxidize FA and xenobiotic compounds that are poor substrates for mitochondrial enzymes. Peroxisomal β-oxidation may play a role as an “overflow” pathway to oxidize FA during extensive NEFA mobilization. In laboratory rodents, peroxisomal β-oxidation peroxisomal β-oxidation is induced by dietary fat, starvation, uncontrolled diabetes, and numerous compounds known as peroxisomal proliferators, with the best known being clofibrate. PROLIFERADORES PEROXISOMALES

32 HEPAGEN Active substance: Phenoxy-2-methyl-2 propionic acid O C CH3 OH

33 HEPAGEN Hepagen actúa ligando PPARα (Peroxisome Proliferator Activated Receptor alpha) Un receptor nuclear perteneciente a la familia PPAR Receptores que juegan un rol central en la coordinación del balance energético

34 Peroxisome proliferator activated receptors (PPARs)
3 isotipos principales: PPARα, PPARδ (or β), PPARγ Factores de Transcripción Una vez activados, los PPAR`s se ligan al ADN y regulan la transcripción de los genes Los ligantes para los PPAR`s son los ácidos grasos libres y los eicosanoides Genes Enzimas PPARα is activated by leukotriene B4 Metabolismo 

35 HEPAGEN: Mecanismo de Acción
Activados por Hepagen, el PPARα interactúa con RXR y despues, ligandose a elementos Específicos de Respuesta (PPREs) regula la expresión de un conjunto de genes involucrados en el catabolismo de los ácidos grasos RXR: Retinoid X Receptor Figure 1. Schematic representation of the fibrate effect. Acting as an agonist for peroxisome proliferator activated receptor alfa (PPARalfa) receptor, Hepagen induces the formation of a nuclear transcription complex, including the heterodimer PPAR-alpha/retinoid X receptor (RXR). Promoter regions containing the PPAR regulatory element will bind the complex, which will result in the modulation (up- or downregulation) of the transcription rate of the downstream gene. (PPRE— peroxisome proliferator response element.)

36 PPARα Un regulador central del metabolismo lipídico hepático
Control del transporte y consumo de los ácidos grasos Activación de ácidos grasos de larga cadena en Acyl-CoA (Acyl-CoA sintetasa) Enzimas involucradas en la β-oxidación Metabolismo de las Lipoproteínas target genes code for several enzymes involved in the β-oxidation pathway, namely acyl-CoA oxidase [49], bifunctional enzyme [50] and thiolase [51]. The activation of long-chain fatty acid into acyl-CoA thioester by the long-chain fatty acyl-CoA synthetase is likely to be regulated by PPARα [52]. PPARα also participates in the control of fatty acid transport and uptake, by stimulating the genes encoding the fatty acid transport protein (FATP), the fatty acid translocase (FAT/CD36) and the liver cytosolic fatty acid-binding protein (L-FABP) (Fig. 2) [53]. The metabolism of triglyceride-rich lipoproteins is modulated by PPARα-dependent stimulation of the lipoprotein lipase gene, which facilitates the release of fatty acids from lipoprotein particles, and the down-regulation of apolipoprotein C-III [54]. Furthermore, PPARα up-regulates apolipoprotein A-I and A-II in humans, which leads to an increase in plasma high-density lipoprotein (HDL) cholesterol. Additional PPARα target genes participate in mitochondrial fatty acid metabolism [55,56], in ketogenesis [57] and in microsomal fatty acid ω-hydroxylation by cytochrome P450 ω-hydroxylases that belong to the CYP4A family [58,59]. Among the key lipid metabolizing extra-hepatic genes activated by PPARα is lipoprotein lipase, involved in the degradation of triglycerides [60]. Hepatic lipogenesis and phospholipid transport (MDR2, ABCB4) are regulated by fibrates [61]. Several bile acid synthetic genes are regulated by PPARα.

37 HEPAGEN La única droga específica para el hígado graso disponible en veterinaria Estimula la β-oxidación peroxisomal y mitocondrial Promueve el catabolismo de los ácidos grasos Reduce la síntesis hepática de triglicéridos Eleva el colesterol HDL (importante en la esteroidogénesis y fertilidad)

38 Estimulante de la capacidad regenerativa del hígado
HEPAGEN Estimulante de la capacidad regenerativa del hígado

39 Intoxicación Amoniacal
Incrementando la capacidad detoxificante del hígado

40 Intoxicación Amoniacal
Hígado graso Acidosis Cetosis Intoxicaciónes Enfermedades infecciosas Raciones bajas en energía digestible Alto nitrógeno no proteico(urea) Exceso de proteína degradable en dieta Disminución de la capacidad de detoxificación hepática In ruminants ammonia is produced during the degradation of proteins in the rumen and in the catabolism of amino acids in tissues In ruminants, hyperammoniemia is often associated with high non-protein nitrogen feeding and nitrogen absorbed as ammonia can be several times the amount absorbed in the form of amino acids or peptides Ammonia intoxication can also results from metabolic disorders, which affects liver detoxifying capacities, or from other hepatic dysfunctions All cows after calving have increased circulating ammonia because of decreased ureagenesis caused by hepatic lipid accumulation Intoxicación Amoniacal Gluconeogénesis a partir de aminoácidos

41 La acumulación de triglicéridos en el hígado reducen la capacidad ureogénica en mas de un 40%
Hepatic triglyceride accumulation from exogenous NEFA reduces ureagenic capacity up to 40%. Strang 1998

42 Intoxicación amoniacal en el periparto
El amoníaco en sangre se duplica cuando se incrementa la concentración de TG en el hígado durante el periparto (Zhu 2000) Las vacas en lactación temprana a menudo consumen mas proteína total y degradable que en el preparto

43 Toxicidad el amoníaco Afecta el metabolismo intermedio
Disminuye la habilidad de los hepatocitos para sintetizar glucosa Incrementa la incidencia de desórdenes metabólicos Reduce la producción de leche Afecta óvulos y embriones y reduce la performance reproductiva

44 Amoníaco inhibe fuertemente la capacidad del hígado de sintetizar glucosa
Conversion of [1-14C]propionate and [1-14C]alanine to glucose by isolated liver cells as affected by addition of NH4Cl in vitro (Overton et al., 1999) (Overton 1999)

45 METABOLASE Acción detoxificante sobre el amoníaco
L-Ornithine L-Citrulline L-Arginine Aspartic acid Glutamic acid L-Carnitine

46 Detoxificación hepática del amoníaco
AMMONIA Aspartic acid Citrulline UREA CYCLE Ornithine Arginine Through hepatic ureogenesis (Urea Cycle), ammonia is transformed into the less toxic compound urea, which is eliminated with the urine The urea cycle is particularly important for ruminants as ammonia is produced in high quantities during fermentation of nitrogenous matter in the rumen UREA La ureogénesis tiene lugar en el hígado y es esencial para la detoxificación del amoníaco

47 Detoxificación extrahepática del amoníaco
ASPARTIC ACID + AMMONIA GLUTAMIC ACID + AMMONIA ASPARAGINE GLUTAMINE It participates in detoxification of ammonia in the organism through asparagine synthesis. In the kidney, asparagine is split into aspartic acid and ammonia which is then eliminated with the urine in the form of ammonium ions (Extrahepatic detoxification of ammonia) AMMONIA Excreción renal

48 Amoníaco Orina UREA CYCLE Aspartic acid Glutamic acid Asparagine
Ornithine Citrulline UREA CYCLE Aspartic acid Glutamic acid Asparagine Glutamine Arginine UREA Amoníaco Orina

49 La administración EV de Carnitina previene la hiperamoninemia en rumiantes
Changes in plasma ammonia N in sheep following i.v. L-carnitine administration and oral urea load test AMMONIA µmol/L Changes in plasma ammonia N in sheep following i.v. L-carnitine administration and oral urea load test. Control Carnitine Chapa 1998 Time, minutes

50 Estrés Oxidativo El último desafío

51 ROS y radicales libres Estrés Oxidativo
Especies de Oxígeno Reactivo (ROS) son productos intermedios del metabolismo oxidativo Estrés Oxidativo Los ROS se generan mas rapidamente de lo que pueden ser neutralizados por los mecanismos antioxidantes

52 Origen de ROS Continuamente producidos por las células y removidos por los sistemas antioxidantes de defensa Producción de energía en la mitocondria Algunas reacciones enzimáticas Procesos de detoxificación Respuesta inmune

53 Toxicidad por ROS Alta predisposición para interactuar con otras moléculas Causan notable daño a las células y tejidos Los ROS son dañinos bajo las llamadas condiciones estresantes Inflamaciones, Infecciones Estrés ambiental Vacas de alta producción Health and performance of dairy cows suffer when reactive oxygen species (ROS) are generated faster than they can be safely neutralized by antioxidant mechanisms

54 Mitocondria y Estrés oxidativo
La mitocondria es una importante fuente de ROS La cadena respiratoria continuamente libera radicales libres Electron transport FREE RADICALS Within eukaryotic cells mitochondria provide most of the ATP by oxidative phosphorylation. In addition, mitochondria are critical for other aspects of cell function, such as haem and iron sulphur centre biosynthesis and modulating calcium levels. Consequently mitochondrial dysfunction arising from oxidative damage and mutations to mitochondrial and nuclear genes contributes to a wide range of human diseases, including neurodegenerative diseases, ischaemia-reperfusion injury in stroke and heart attack, diabetes and the cumulative degeneration associated with ageing. This mitochondrial dysfunction causes cell damage and death by compromising ATP production, disrupting calcium homeostasis and increasing oxidative stress. Furthermore mitochondrial damage can lead to apoptotic cell death by causing the release of cytochrome c and other pro-apoptotic factors into the cytoplasm. Oxidative stress is a particularly important factor in mitochondrial dysfunction because the respiratory chain continually leaks the free radical superoxide. Another radical that interacts with mitochondrial metabolism is nitric oxide which can react with superoxide to form the damaging byproduct peroxynitrite. These reactive oxygen species lead to generalised oxidative damage to all mitochondrial components, including an increased mutation rate for mitochondrial DNA relative to nuclear DNA. Mitochondrial DNA encodes 13 peptide components of oxidative phosphorylation complexes and the RNA machinery necessary for their translation. Therefore damage to mitochondrial DNA disrupts mitochondrial oxidative phosphorylation, contributing to a number of human diseases. percentage of oxygen converted to superoxide increases with age (3–6). This leads to a vicious cycle of increasing mitochondrial damage, which adversely affects cell function (7), and results in a loss of ATP-generating capacity, especially in times of greater energy demand, thereby compromising vital ATP-dependent reactions. Cellular processes affected by mitochondrial decay include detoxification, repair systems, DNA replication, osmotic balance, and higher-order processes (7), such as cognitive function (7–9). Thus, preservation of mitochondrial function important for maintaining overall health during aging (7). This Calcium Desórdenes Metabólicos ATP Cell Cell Damage

55 Estrés oxidativo durante la respuesta inmune
Neutrófilos producen grandes cantidades de superóxidos y peróxidos de hidrógeno para destruir organismos extraños Phospolipase A2 activity Leukotrienes Lipid Peroxidation OH. H2O2 O2- H2O + O2 + Stimulant Phagosome H+ (PMA) H2O2 O2 SOD Catalase PKC O2- O2- SOD GSSG H2O2 NADPH GP Oxidase GR GSH H2O NADPH + H+ La respuesta inmune humoral y celular es deteriorada por los ROS NADP+ HMP

56 Estrés oxidativo y Enfermedades Metabólicas
Estrecha relación entre estrés oxidativo y la recuperación de enfermedades metabólicas Los ROS afectan: La función mitocondrial La respuesta inmune La perfusión tisular La actividad enzimática El ADN Las membranas lipídicas

57 METABOLASE Actividad antioxidante
L-Carnitina Ác. Tióctico Glicina

58 El ác. Araquidónico y el estrés oxidativo
Membrane Phospholipids El ác. Araquidónico juega un importante rol en la inflamación El ác. Araquidónico juega un importante rol en la producción de radicales libres vía el sistema NADPH oxidasa PL PG LT NADPH Oxidase Oxidative stress Inflammation

59 Efecto de la Carnitina sobre el metabolismo del ác. Araquidónico
Membrane Phospholipids Carnitina reduce la disponibilidad de ác.araquidónico y el estrés oxidativo (Pignatelli 2003) PL AA CARNITINE Pignatelli P, Lenti L, Sanguigni V, Frati G, Simeoni I, Gazzaniga PP, Pulcinelli FM, Violi F. Carnitine inhibits arachidonic acid turnover, platelet function, and oxidative stress. Am J Physiol Heart Circ Physiol Jan;284(1):H41-8. Epub 2002 Sep 05. Diagram showing the effect of carnitine on AA metabolism. Owing to platelet activation PLA2 and PLC induce a release of AA from phospholipids that was shifted by carnitine from its physiological activation pathways. As a consequence, thromboxane formation and NADPH oxidase system activation are both inhibited, and, in turn, platelet activation is negatively modulated. NADPH Oxidase PG LT β-OXIDATION Oxidative stress Inflammation

60 Ácido Tióctico o Lipoico
Pasando de disulfidrilo a disulfuro y viceversa ,éste es un eficiente sistema de óxido reducción

61 Ácido Tióctico/Lipoico El antioxidante ideal
Único por su capacidad de actuar como antioxidante tanto en grasa como en agua Elimina la mayoría de los ROS Es capaz de regenerar la Vit.C, Vit.E y el Glutatión Tiene acción quelante sobre metales

62 Glicina Glicina, un simple aminoácido no esencial, es un bien conocido inhibidor de la neurotransmisión, que actúa vía un canal de cloro Las células de Kupffer y otros macrófagos expresan un canal de cloro que la glicina bloquea El efecto inhibitorio de la glicina en éstas células reduce la producción de ROS y citoquinas

63 Mecanismo de acción de la Glicina
ROS y citoquinas

64

65 El rol antiesteatósico de los Proliferadotes Peroxisomales
Regulador específico el metabolismo lipídico Promueve el catabolismo de los Ácidos Grasos Combate el Hígado Graso y los desórdenes metabólicos asociados

66 ¿Cuándo tratar? Metabolase & Hepagen

67 Indicaciones Tratamiento preventivo al secado de las vacas
Desórdenes en el Periparto (Fiebre de leche, Cetosis, Desplazamiento de Abomaso, Retención de Placenta, Mastitis) Programas Médicos de la vaca recién parida

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