ES2322685B2 - USE OF LOW DOSE OF IGF-II IN AGING FOR ITS NEUROPROTECTORS AND HEPATOPROTECTORS EFFECTS. - Google Patents
USE OF LOW DOSE OF IGF-II IN AGING FOR ITS NEUROPROTECTORS AND HEPATOPROTECTORS EFFECTS. Download PDFInfo
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- ES2322685B2 ES2322685B2 ES200603020A ES200603020A ES2322685B2 ES 2322685 B2 ES2322685 B2 ES 2322685B2 ES 200603020 A ES200603020 A ES 200603020A ES 200603020 A ES200603020 A ES 200603020A ES 2322685 B2 ES2322685 B2 ES 2322685B2
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/30—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/65—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Utilización de dosis bajas de IGF-II en el envejecimiento por sus efectos neuroprotectores y hepatoprotectores.Use of low doses of IGF-II in aging due to its effects neuroprotectors and hepatoprotectors.
La presente invención se refiere a la administración de IGF-II en dosis bajas en el envejecimiento por sus efectos neuroprotectores y hepatoprotectores, y concretamente a su uso en la elaboración de medicamentos o composiciones farmacéuticas con efecto neuroprotector y hepatoprotector. En particular, la aplicación de la presente invención se refiere a mamíferos, incluyendo obviamente al ser humano. El tratamiento sustitutivo o compensatorio con IGF-II normaliza la glucemia, disminuye los niveles de triglicéridos y de colesterol, sin modificar las concentraciones plasmáticas de IGF-I y de testosterona. En resumen, la administración de IGF-II, a dosis bajas, induce efectos antioxidantes, neuroprotectores y hepatoprotectores, mejorando la función mitocondrial.The present invention relates to the administration of IGF-II at low doses in the aging due to its neuroprotective and hepatoprotective effects, and specifically its use in the preparation of medicines or pharmaceutical compositions with neuroprotective effect and hepatoprotective In particular, the application of this invention refers to mammals, obviously including being human. Substitute or compensatory treatment with IGF-II normalizes blood glucose, lowers levels of triglycerides and cholesterol, without changing concentrations plasma IGF-I and testosterone. In summary, administration of IGF-II, at low doses, induces antioxidant, neuroprotective and hepatoprotective effects, improving mitochondrial function.
Description
Utilización de dosis bajas de IGF-II en el envejecimiento por sus efectos neuroprotectores y hepatoprotectores.Use of low doses of IGF-II in aging due to its effects neuroprotectors and hepatoprotectors.
La presente invención se engloba en el sector de las preparaciones de uso médico relacionadas con la actividad terapéutica de compuestos o composiciones.The present invention is included in the sector of preparations for medical use related to the activity Therapeutics of compounds or compositions.
IGF- II es una hormona peptídica, de 67 aminoácidos, que pertenece a la familia de los Insulin-like growth factors (Molecular and Cellular Endocrinology, 1993, 92: C1-C3). Tiene un papel importante en el desarrollo embrionario (Cytokine and Growth Factor Reviews, 1997, 8: 45-62). Por ello, la expresión de mRNA IGF II es muy elevada en la mayoría de los tejidos fetales y parece estar inducida por el lactógeno placenario (Cytokine and Growth Factor Reviews, 1997, 8: 45-62). IGF II es un péptido relacionado con la acción de la hormona del crecimiento, GH (Pediatrician, 1987, 14: 154-161). Es secretado por el hígado y otros tejidos y está postulado que tiene acciones metabólicas y mitogénicas (Vitamines and Hormones, 1993, 47: 1-114). Sin embargo, se desconocen las funciones fisiológicas de IGF-II en la vida adulta (Molecular and Cellular Endocrinology, 1993, 92: C1-C3).IGF-II is a 67 amino acid peptide hormone, which belongs to the family of Insulin-like growth factors (Molecular and Cellular Endocrinology, 1993, 92: C1-C3). It has an important role in embryonic development (Cytokine and Growth Factor Reviews, 1997, 8: 45-62). Therefore, the expression of IGF II mRNA is very high in most fetal tissues and appears to be induced by the placenary lactogen (Cytokine and Growth Factor Reviews, 1997, 8: 45-62). IGF II is a peptide related to the action of growth hormone, GH (Pediatrician, 1987, 14: 154-161). It is secreted by the liver and other tissues and it is postulated that it has metabolic and mitogenic actions (Vitamines and Hormones, 1993, 47: 1-114). However, the physiological functions of IGF-II in adult life are unknown (Molecular and Cellular Endocrinology, 1993, 92: C1-C3).
Esta hormona es capaz de unirse a 4 receptores distintos (receptor de la insulina, receptor IGF tipo I, el receptor IGF híbrido y el receptor IGF tipo II). El receptor tipo 2 está presente en la circulación, hendido en la superficie de la célula. De esta forma, el receptor tipo 2 transportaría gran cantidad de IGF II, especialmente en la circulación fetal, por lo que podría funcionar como proteína transportadora del IGF II.This hormone is able to bind to 4 different receptors (insulin receptor, type I IGF receptor, hybrid IGF receptor and type II IGF receptor). The type 2 receptor is present in the circulation, cleft on the surface of the cell. In this way, the type 2 receptor would transport a large amount of IGF II, especially in the fetal circulation, so it could function as a transporter protein for IGF II.
Aunque este factor de crecimiento ha sido menos estudiado que el IGF-I, su papel como regulador del crecimiento fetal y placentario ha sido demostrado en numerosos estudios (Pediatrician, 1987, 14: 154-161), aunque dicha caracterización es aún insuficiente. Posee efectos metabólicos como la estimulación del transporte y la utilización de la glucosa, del transporte de aminoácidos y de la síntesis de proteínas. También se han descrito efectos promotores del crecimiento, estando involucrado en la estimulación de la síntesis de DNA y RNA y la proliferación, diferenciación y supervivencia celular. Estos efectos están mediados por la interacción de IGF-II con el receptor de IGF tipo 1 y el receptor de la insulina (Cytokine and Growth Factor Reviews, 1997, 8: 45-62).Although this growth factor has been less studied that IGF-I, its role as regulator of fetal and placental growth has been demonstrated in numerous studies (Pediatrician, 1987, 14: 154-161), although This characterization is still insufficient. It has effects metabolic as the stimulation of transport and the use of glucose, amino acid transport and synthesis of proteins Promotional effects of the growth, being involved in the stimulation of synthesis of DNA and RNA and proliferation, differentiation and survival mobile. These effects are mediated by the interaction of IGF-II with type 1 IGF receptor and receiver of insulin (Cytokine and Growth Factor Reviews, 1997, 8: 45-62).
La función del IGF II no ha sido aún
estrictamente establecida, aunque se sabe que depende de las
concentraciones de GH y otros factores (Phyiologycal Reviews, 1990,
70: 591-613). La expresión postnatal del gen de IGF
II es asumida por el promotor hígado específico P1, y como
resultado hay unos elevados niveles de IGF II en suero que aumentan
hasta la pubertad, y que van declinando con la edad (Molecular and
Endocrinology, 1993, 92:
C1-C3).The role of IGF II has not yet been strictly established, although it is known to depend on the concentrations of GH and other factors (Phyiologycal Reviews, 1990, 70: 591-613). The postnatal expression of the IGF II gene is assumed by the specific liver promoter P1, and as a result there are high levels of serum IGF II that increase until puberty, and that decline with age (Molecular and Endocrinology, 1993, 92 :
C1-C3).
En el sistema nervioso adulto, el IGF II no ha sido suficientemente estudiado, aunque se sabe que existen abundantes receptores en los plexos coroideos y que es muy frecuente en otras estructuras de sostén como las meninges y la red vascular. También está presente en el hipocampo y en la corteza cerebral en regiones superficiales y, en general, es más abundante en áreas compuestas por cuerpos neuronales.In the adult nervous system, IGF II has not been sufficiently studied, although it is known that they exist abundant receptors in the choroid plexus and that is very frequent in other support structures such as the meninges and the vascular network. It is also present in the hippocampus and in the cerebral cortex in surface regions and, in general, is more abundant in areas composed of neuronal bodies.
Las situaciones de deficiencia de IGF-I, en las cuales el tratamiento sustitutivo podría ser una estrategia terapéutica eficaz, son poco conocidas. De las situaciones de deficiencia de IGF-I, la mejor conocida es el Síndrome de Laron o Enanismo de Laron (The New England Journal of Medicine, 1996, 334: 463-465), caracterizada por una alteración genética que condiciona la ausencia de receptores para la GH en hígado, con la correspondiente deficiencia de IGF-I, mientras que existen niveles normales o incluso altos de GH. La deficiencia de IGF-I causa el enanismo y falta de desarrollo de estos niños. El tratamiento sustitutivo con IGF-I normaliza el crecimiento y el desarrollo (Journal of Pediatric Endocrinology and Metabolism, 1995, 8: 149-158).The deficiency situations of IGF-I, in which substitute treatment It could be an effective therapeutic strategy, they are little known. Of the IGF-I deficiency situations, the best known is Laron Syndrome or Laron Dwarfism (The New England Journal of Medicine, 1996, 334: 463-465), characterized by a genetic alteration that conditions the absence of receptors for GH in liver, with the corresponding IGF-I deficiency, while levels exist normal or even high GH. Deficiency of IGF-I causes dwarfism and lack of development of these children. Substitute treatment with IGF-I normalizes growth and development (Journal of Pediatric Endocrinology and Metabolism, 1995, 8: 149-158).
Otra condición de deficiencia de IGF-I, en este caso en la edad adulta, es la cirrosis hepática: el hígado en la medida que se fibrosa, pierde receptores para la GH y las amplias zonas de necrosis, o de parénquima mal irrigado, comprometen progresivamente la capacidad biosintética del hígado. El IGF-I es una de la muchas proteínas hepáticas que ven comprometida su síntesis en la cirrosis hepática. La deficiente síntesis de IGF-I en la cirrosis hepática fue descrita por Wu y colaboradores (Clinical Science and Molecular Medicine, 1974, 47: 359-366).Another condition of deficiency of IGF-I, in this case in adulthood, is the liver cirrhosis: the liver as it is fibrous, loses receptors for GH and broad areas of necrosis, or of poorly irrigated parenchyma, progressively compromise the ability Biosynthetic liver. IGF-I is one of the many liver proteins whose synthesis is compromised in the hepatic cirrhosis. The poor synthesis of IGF-I in liver cirrhosis was described by Wu et al. (Clinical Science and Molecular Medicine, 1974, 47: 359-366).
Sin embargo, no se estableció que la cirrosis era una situación de "deficiencia de IGF-I" hasta que vinculamos esa deficiente síntesis de IGF-I con la desnutrición progresiva que experimenta el paciente cirrótico. Tras intuir esta relación pudimos caracterizar la cirrosis hepática avanzada como una condición de deficiencia de IGF-I y proponer la terapia sustitutiva como una estrategia terapeútica. En efecto, ese tratamiento a dosis bajas, indujo efectos hepatoprotectores y antifibrogénicos y múltiples acciones sistémicas, anabolizantes y antioxidantes: mejorando el estado nutricional, la absorción intestinal de aminoácidos y azúcares, la osteopenia y el hipogonadismo (Gastroenterology, 1997, 113: 1180-1187 y 1682-1691; Journal of Hepatology, 1997, 26: 191-202; Journal of Hepatology, 1998, 28: 122-131; Journal of Physiology and Biochemistry, 2000, 56: 91-99; Hepatology, 2000, 31: 592-600; Liver, 2001, 37: 215-219; International Journal of Biochemistry and Cellular Biology, 2002, 34: 242-252; Journal of Physiology and Biochemistry, 2003, 59: 115-118; WJ Gastroenterology, 2004, 10: 2529-2534; BMC Gastroenterology, 2004, 4: 12-20; BMC Gastroenterology, 2005, 5: 7-14; Biochimica et Biophysica Acta, 2001, 1536: 185-195; Journal of Hepatology, 2005, 14: 118-125).However, it was not established that cirrhosis it was a situation of "IGF-I deficiency" until we link that poor synthesis of IGF-I with progressive malnutrition that The cirrhotic patient experiences. After intuiting this relationship we could characterize advanced liver cirrhosis as a condition of IGF-I deficiency and propose therapy substitute as a therapeutic strategy. Indeed that low dose treatment, induced hepatoprotective effects and antifibrogenic and multiple systemic, anabolic and antioxidants: improving nutritional status, absorption intestinal amino acids and sugars, osteopenia and hypogonadism (Gastroenterology, 1997, 113: 1180-1187 and 1682-1691; Journal of Hepatology, 1997, 26: 191-202; Journal of Hepatology, 1998, 28: 122-131; Journal of Physiology and Biochemistry, 2000, 56: 91-99; Hepatology, 2000, 31: 592-600; Liver, 2001, 37: 215-219; International Journal of Biochemistry and Cellular Biology, 2002, 34: 242-252; Journal of Physiology and Biochemistry, 2003, 59: 115-118; Wj Gastroenterology, 2004, 10: 2529-2534; BMC Gastroenterology, 2004, 4: 12-20; BMC Gastroenterology, 2005, 5: 7-14; Biochimica et Biophysica Acta, 2001, 1536: 185-195; Journal of Hepatology, 2005, 14: 118-125).
Además de la importancia del hígado como glándula endocrina, de estos resultados se dedujo el relevante papel de la GH en el organismo adulto. Es precisa la adecuada función de eje GH-IGF-I para el buen estado funcional de múltiples órganos y tejidos por los efectos anabolizantes y antioxidantes de esta hormona de síntesis hepática. Estos y otro datos propician abordar una tercera condición de deficiencia de IGF-I: el envejecimiento.In addition to the importance of the liver as endocrine gland, from these results the relevant role of GH in the adult organism. The right one is accurate GH-IGF-I axis function for the good functional status of multiple organs and tissues due to the effects Anabolic and antioxidants of this liver synthesis hormone. These and other data favor addressing a third condition of IGF-I deficiency: aging.
Efectivamente, con la edad el eje GH-IGF-I experimenta un declive (Journal of Endocrinology Investigation, 2005, 28: 94-98 y 99-108): 1) disminuye la amplitud, el pulso y la fracción de GH; 2) paralelamente, acontece una progresiva disminución de las concentraciones de IGF-I.Indeed, with age the axis GH-IGF-I experiences a decline (Journal of Endocrinology Investigation, 2005, 28: 94-98 and 99-108): 1) decreases the amplitude, pulse and fraction of GH; 2) in parallel, it happens a progressive decrease in concentrations of IGF-I.
Por lo tanto, se pueden distinguir tres premisas de interés:Therefore, three premises can be distinguished of interest:
- \bullet?
- En el envejecimiento, existe una disminución de IGF-I y de GH. In aging, there is a decrease in IGF-I and GH.
- \bullet?
- El estrés oxidativo es un mecanismo causal del envejecimiento tisular y de la muerte celular. Oxidative stress is a causal mechanism of tissue aging and death mobile.
- \bullet?
- La administración de IGF-I en una situación de deficiencia de dicha hormona, como es la cirrosis hepática, puede causar un efecto antioxidante. The administration of IGF-I in a situation of deficiency of said hormone, such as liver cirrhosis, can cause an effect antioxidant
Por otra parte, la amplia difusión de receptores para IGF-I y de IGF-II en el cerebro y en médula espinal, permitían suponer que estos efectos pudieran ser similares en el SNC (Endocrinology, 1988, 1123: 2089-2099). Además, existían antecedentes demostrando los efectos neuroprotectores y neurotróficos de esta hormona (Brain Research, 2003, 991: 34-45; Progress in Neurobiology, 2003, 70: 443-462; Brain Research and Molecular Brain Research, 2004, 131: 33-50; Neuroreport, 2004, 15: 2251-4; Brain Research, 2004, 1009: 213-218; European Journal of Pharmacology, 2004, 490: 25-31; Journal of Neuroscience Research, 2004, 76: 98-103; European Journal of Neuroscience, 2005, 21: 1489-1502).Moreover, the wide diffusion of receivers for IGF-I and IGF-II in the brain and in the spinal cord, they allowed us to assume that these effects could be similar in the SNC (Endocrinology, 1988, 1123: 2089-2099). In addition, there was a background demonstrating the neuroprotective and neurotrophic effects of this hormone (Brain Research, 2003, 991: 34-45; Progress in Neurobiology, 2003, 70: 443-462; Brain research and Molecular Brain Research, 2004, 131: 33-50; Neuroreport, 2004, 15: 2251-4; Brain Research, 2004, 1009: 213-218; European Journal of Pharmacology, 2004, 490: 25-31; Journal of Neuroscience Research, 2004, 76: 98-103; European Journal of Neuroscience, 2005, 21: 1489-1502).
La presente invención se refiere a la administración del factor de crecimiento semejante a la insulina tipo II (IGF-II) en dosis bajas en el envejecimiento por sus efectos neuroprotectores y hepatoprotectores, y a su uso en la elaboración de productos con efecto neuroprotector y hepatoprotector. En particular, la aplicación de la presente invención se refiere a mamíferos, incluyendo obviamente al ser humano.The present invention relates to the administration of insulin-like growth factor Type II (IGF-II) in low doses in aging for its neuroprotective and hepatoprotective effects, and its use in the elaboration of products with neuroprotective effect and hepatoprotective In particular, the application of this invention refers to mammals, obviously including being human.
En el envejecimiento se aprecia la deficiencia de la hormona IGF-I y de la capacidad antioxidante a la vez que un aumento significativo de la glucemia, la colesterolemia, la peroxidación lipídica, así como en las concentraciones de triglicéridos. El tratamiento sustitutivo o compensatorio con IGF-II normaliza la glucemia, disminuye los niveles de triglicéridos y de colesterol, sin modificar las concentraciones plasmáticas de IGF-I y de testosterona.In aging the deficiency can be seen of the hormone IGF-I and antioxidant capacity while a significant increase in blood glucose, the cholesterolemia, lipid peroxidation, as well as in triglyceride concentrations. The substitute treatment or compensatory with IGF-II normalizes blood glucose, lowers triglyceride and cholesterol levels without modify plasma concentrations of IGF-I and of testosterone.
En resumen, la administración de IGF-II, a dosis bajas, induce efectos antioxidantes, neuroprotectores y hepatoprotectores, mejorando la función mitocondrial.In short, the administration of IGF-II, at low doses, induces antioxidant effects, neuroprotectors and hepatoprotectors, improving function mitochondrial
Tabla 1. Pruebas analíticas en suero. Concentraciones de glucosa, colesterol, triglicéridos, alanina transaminasa (ALT), aspartato transaminasa (AST), fosfatasa alcalina (FA), y proteínas totales determinados en muestras de suero de animales jóvenes (COj), animales viejos tratados con IGF-II (V+IGF-II) y tratados con solución salina (V). X\pmESM; *p<0.05 ***p<0.001 vs COj.Table 1. Analytical tests in serum. Glucose, cholesterol, triglycerides, alanine concentrations transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (FA), and total proteins determined in serum samples of young animals (COj), old animals treated with IGF-II (V + IGF-II) and treated with saline solution (V). X ± ESM; * p <0.05 *** p <0.001 vs COj.
Tabla 2. Actividad específica de enzimas antioxidantes en cerebro (córtex e hipocampo), incluyendo catalasa, superóxido dismutasa (SOD), Glutatión peroxidasa (GPX) y GRD; en animales jóvenes (COj), animales viejos tratados con IGF-II (V+IGF-II) y tratados con solución salina (V). X\pmESM; *p<0.05, **p<0.01, ***p<0.001 vs COj; ^{&}p<0.05, ^{&&}p<0.01 vs V.Table 2. Specific enzyme activity antioxidants in the brain (cortex and hippocampus), including catalase, superoxide dismutase (SOD), Glutathione peroxidase (GPX) and GRD; in young animals (COj), old animals treated with IGF-II (V + IGF-II) and treated with saline solution (V). X ± ESM; * p <0.05, ** p <0.01, *** p <0.001 vs COj; ^ p <0.05, ^ {&&} p <0.01 vs V.
Figura 1. Daño oxidativo en cerebro - Concentraciones de MDA, marcador de peroxidación lipídica, y contenido de proteínas carboxiladas en córtex cerebral (A y C, respectivamente) e hipocampo (B y D, respectivamente), en animales jóvenes (COj), animales viejos tratados con IGF-II (V+IGF-II) y tratados con solución salina (V). (A) X \pm ESM; *p<0,05 vs COj; & V+IGF-II; (B) X \pm ESM; *p<0,05 vs COj; & V+IGF-II; (C) X f ESM; **p<0,01 vs : COj; y (D) X \pm ESM; *p<0,05 vs COj.Figure 1. Oxidative damage in brain - MDA concentrations, lipid peroxidation marker, and carboxylated protein content in cerebral cortex (A and C, respectively) and hippocampus (B and D, respectively), in animals young (COj), old animals treated with IGF-II (V + IGF-II) and treated with saline (V). (A) X ± ESM; * p <0.05 vs COj; & V + IGF-II; (B) X ± ESM; * p <0.05 vs COj; & V + IGF-II; (C) X f ESM; ** p <0.01 vs: COj; and (D) X ± ESM; * p <0.05 vs COJ.
Figura 2. Actividad específica de superóxido dismutasa (SOD) en hipocampo (A), y correlación directa y significativa entre la actividad específica de la enzima superóxido dismutasa (SOD) con el marcador de peroxidación lipídica MDA (B).Figure 2. Specific superoxide activity dismutase (SOD) in hippocampus (A), and direct correlation and significant among the specific activity of the superoxide enzyme dismutase (SOD) with the MDA lipid peroxidation marker (B).
Figura 3. Daño oxidativo, en función de la peroxidación lipíca (A) y contenido de proteínas carboxiladas (B) en tejido hepático. (A) X \pm ESM; ***p<0,001 vs COj.Figure 3. Oxidative damage, as a function of lipid peroxidation (A) and carboxylated protein content (B) in liver tissue. (A) X ± ESM; *** p <0.001 vs COj.
Figura 4. Potencial de membrana mitocondrial, evaluado por citometria de flujo con rodamina 123, en mitocondrias aisladas en animales jóvenes (COj), animales viejos tratados con IGF-II (V+IGF-II) y tratados con solución salina (V), según las diferentes condiciones (sustratos).Figure 4. Mitochondrial membrane potential, evaluated by flow cytometry with rhodamine 123, in mitochondria isolated on young animals (COj), old animals treated with IGF-II (V + IGF-II) and treated with saline solution (V), according to the different conditions (substrates).
Figura 5. Estudio del potencial de membrana mitocondrial, evaluado de igual forma que se explica en la figura 4, en animales jóvenes (COj), animales viejos tratados con IGF-II (V+IGF-II) y tratados con solución salina (V), según las diferentes condiciones: (A) Estado 4 (X \pm ESM **p<0,01 V vs COj; &p<0,05 V+IGF-II vs V), (B) Estado 3 (X \pm ESM; **p<0,01 V vs COj), y (C) con oligomicina (X \pm ESM; *p<0,05 V vs COj).Figure 5. Study of membrane potential mitochondrial, evaluated in the same way as explained in the figure 4, in young animals (COj), old animals treated with IGF-II (V + IGF-II) and treated with saline solution (V), according to the different conditions: (A) State 4 (X ± ESM ** p <0.01 V vs COj; & p <0.05 V + IGF-II vs V), (B) State 3 (X ± ESM; ** p <0.01 V vs COj), and (C) with oligomycin (X ± ESM; * p <0.05 V vs COj).
Figura 6. Síntesis de ATP en animales jóvenes (COj), animales viejos tratados con IGF-II (V+IGF-II) y tratados con solución salina (V). X \pm ESM; *p<0,05 V vs otros grupos.Figure 6. Synthesis of ATP in young animals (COj), old animals treated with IGF-II (V + IGF-II) and treated with saline (V). X ± ESM; * p <0.05 V vs other groups.
Figura 7. Producción intramitocondrial de radicales libres (peróxido de hidrógeno). X \pm ESM; ***p<0,001 V vs otros grupos.Figure 7. Intramitochondrial production of free radicals (hydrogen peroxide). X ± ESM; *** p <0.001 V vs other groups.
A continuación se describe un estudio del efecto del tratamiento con IGF-II en animales viejos, en concreto usando ratas Wistar macho. No obstante, el presente modo de realización no pretende ser limitativo en relación con el alcance de la invención.A study of the effect of IGF-II treatment in old animals, specifically using male Wistar rats, is described below. However, the present embodiment is not intended to be limiting in relation to the scope of the invention.
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Para caracterizar el modelo se estudiaron controles sanos de edades progresivamente mayores (9, 7, 19, 35, 90 y 103 semanas). Se estudió la evolución de peso corporal o el incremento de peso; las concentraciones de IGF-I y testosterona; y el estado total antioxidante en suero. Así, se estimó que animales con 9 semanas de edad eran demasiado jóvenes, mientras que las 17 semanas era una edad adecuada para considerarlos Controles jóvenes (COj), y 103 semanas de edad podían considerarse de edad suficientemente avanzada, como para evaluar el declive de hormonas anabolizantes y de la capacidad antioxidante. Para estudiar los posibles efectos de IGF-II sobre los animales viejos se realizó (una vez seleccionada la edad de los controles) el siguiente diseño experimental:To characterize the model they were studied healthy controls of progressively older ages (9, 7, 19, 35, 90 and 103 weeks). The evolution of body weight or the Increased weight; IGF-I concentrations and testosterone; and the total antioxidant state in serum. Thus estimated that animals with 9 weeks of age were too young, while the 17 weeks was an adequate age to consider them Young controls (COj), and 103 weeks of age could be considered old enough to assess the decline of anabolic hormones and antioxidant capacity. For study the possible effects of IGF-II on old animals was performed (once the age of the controls) the following experimental design:
- Controles Jóvenes (COj).- Young Controls (COj).
- Animales viejos de 103 semanas de edad que se distribuyeron por el peso corporal en dos grupos idénticos: uno recibiría IGF-II a dosis de 2 mg por 100 g de peso corporal y por día durante 31 días (V+IGF-II); y el otro grupo recibiría solución salina (V).- 103 week old animals that are distributed by body weight in two identical groups: one would receive IGF-II at a dose of 2 mg per 100 g of weight body and per day for 31 days (V + IGF-II); and the another group would receive saline solution (V).
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Se incluyeron en el estudio 30 ratas Wistar macho distribuidas en los tres grupos experimentales descritos. Después del tratamiento, día 32, se sacrificaron todos los animales.Thirty male Wistar rats distributed in the three experimental groups described were included in the study. After treatment, day 32, all animals were sacrificed.
Se separó el suero por centrifugación tras extraer la sangre del plexo retrocular; se diseccionó el hígado y el cerebro y se conservaron muestras por separado de corteza e hipocampo: a -80º tras la inmersión en N líquido. En 5 animales por grupo, una parte del hígado fresco se empleó para aislar mitocondrias y realizar el estudio de función mitocondrial por citometría de flujo.Serum was separated by centrifugation after draw blood from the retrocular plexus; the liver was dissected and the brain and samples were kept separately from cortex e hippocampus: at -80º after immersion in liquid N. In 5 animals per group, a part of the fresh liver was used to isolate mitochondria and perform the study of mitochondrial function by flow cytometry.
Para evaluar el daño oxidativo y las defensas antioxidantes de los animales viejos (tratados y sin tratar con IGF-II) se estudiaron los siguientes parámetros, en homogeneizados de cerebro (corteza e hipocampo) y hepáticos: 1) el grado de peroxidación lipídica: Maloldialdehido (Clinical Chemistry, 1995, 41: 1819-1828; Gastroenterology, 1997, 113: 1682-1691) el grado de carboxilación de proteínas (Protein carboxil content o PCC) (Clinical Chemistry, 1995, 41: 1819-1928); y 3) la actividad específica de las principales enzimas antioxidantes (Gastroenterology, 1997, 113: 1682-1691): superóxido dismutasa (SOD), catalasa y Glutatión peroxidbsa (GSHPx).To evaluate the oxidative damage and antioxidant defenses of old animals (treated and untreated with IGF-II) the following parameters were studied, in brain homogenates (cortex and hippocampus) and liver: 1) the degree of lipid peroxidation: Maloldialdehyde (Clinical Chemistry, 1995, 41: 1819-1828; Gastroenterology, 1997, 113: 1682-1691) the degree of carboxylation of proteins ( Protein carboxy content or PCC) (Clinical Chemistry, 1995, 41: 1819-1928); and 3) the specific activity of the main antioxidant enzymes (Gastroenterology, 1997, 113: 1682-1691): superoxide dismutase (SOD), catalase and Glutathione peroxidbsa (GSHPx).
La función mitocondrial fue evaluada por citometría de flujo (EPICS XL, Coulter) tal y como se describe en trabajos previos (Clinical Chemistry, 1995, 41: 1819-1828; Gastroenterology, 1997, 113: 1682-1691). Se determinó: 1) el Potencial de membrana mitocondrial (PMM), con los diferentes substratos, en presencia del fluorocromo rodamina 123 (Rh123); 2) Síntesis de ATP; 3) Producción de radicales libres intramitocondriales (H_{2}CMXRos).Mitochondrial function was evaluated by flow cytometry (EPICS XL, Coulter) as described in previous work (Clinical Chemistry, 1995, 41: 1819-1828; Gastroenterology, 1997, 113: 1682-1691). It was determined: 1) the Potential of mitochondrial membrane (PMM), with different substrates, in presence of fluorochrome rhodamine 123 (Rh123); 2) Synthesis of ATP; 3) Production of intramitochondrial free radicals (H2 CMXRos).
Las determinaciones hormonales se realizaron por RIA, el estado antioxidante total y las determinaciones analíticas en suero según los métodos colorimétricos previamente descritos (Clinical Chemistry, 1995, 41: 1819-1828: 79; Gastroenterology, 1997, 113: 1682-1691; Journal of Physiology and Biochemistry, 2003, 59: 115-118).Hormonal determinations were performed by RIA, the total antioxidant status and analytical determinations in serum according to the previously described colorimetric methods (Clinical Chemistry, 1995, 41: 1819-1828: 79; Gastroenterology, 1997, 113: 1682-1691; Journal of Physiology and Biochemistry, 2003, 59: 115-118).
Los animales viejos (V) mostraron un aumento significativo de la glucemia, colesterolemia y las concentraciones de triglicéridos (Tabla 1). El tratamiento con IGF-II normalizó la glucemia y redujo los triglicéridos y la colesterolemia.Old animals (V) showed an increase Significant glycemia, cholesterolemia and concentrations of triglycerides (Table 1). Treatment with IGF-II normalized blood glucose and reduced triglycerides and cholesterolemia.
El tratamiento con IGF-II no modificó las concentraciones circulantes de IGF-I, ni de testosterona, en contraste con los resultados obtenidos con la administración de IGF-I. Lo que permite deducir que los posibles efectos anabolizantes o antioxidantes que se describen a continuación se deben a la administración de IGF-II.IGF-II treatment does not modified the circulating concentrations of IGF-I, nor of testosterone, in contrast to the results obtained with the administration of IGF-I. What allows to deduce that the possible anabolic or antioxidant effects that described below are due to the administration of IGF-II
La administración exógena de IGF-II no modificó la capacidad total antioxidante en suero que estaba significativamente reducida en los animales viejos con respecto a los controles jóvenes (en mmol/L, COj=0.91\pm0.01; V=0.84\pm0.01, p<0.001) y que el tratamiento con IGF-I a dosis bajas había logrado normalizar (V+IGF-I=0.88\pm0.02, p<0.01). Sin embargo, el IGF-II indujo los siguientes efectos antioxidantes, neuroprotectores y hepatoprotectores en animales viejos.The exogenous administration of IGF-II did not modify the total antioxidant capacity in serum that was significantly reduced in animals old compared to young controls (in mmol / L, COj = 0.91 ± 0.01; V = 0.84 ± 0.01, p <0.001) and that the treatment with low dose IGF-I he had managed to normalize (V + IGF-I = 0.88 ± 0.02, p <0.01). However the IGF-II induced the following antioxidant effects, neuroprotectors and hepatoprotectors in old animals.
El grado de peroxidación lipídica, estimado por las concentraciones de MDA (Fig. 1A), así como el contenido en proteínas descarboxiladas (PCC, Fig. 1B), fueron significativamente elevados, tanto en corteza como en hipocampo, en los animales viejos, y el tratamiento con IGF-II fue capaz de normalizarlos.The degree of lipid peroxidation, estimated by MDA concentrations (Fig. 1A), as well as the content in decarboxylated proteins (PCC, Fig. 1B), were significantly elevated, both in bark and hippocampus, in animals old, and the IGF-II treatment was able to normalize them
La actividad específica de la SOD en corteza cerebral estuvo significativamente incrementada en el grupo V, mientras los animales viejos tratados con IGF-II presentaron una actividad similar a los COj (Tabla 2). Esta enzima se suele comportar como un marcador de agresión oxidativa. En homogeneizados de hipocampo también se observó un resultado similar en la actividad específica de la SOD (Tabla 2) y, efectivamente, se pudo establecer un estrecha correlación directa con el MDA, marcador de peroxidación lipídica (Fig. 2).The specific activity of bark SOD brain was significantly increased in group V, while old animals treated with IGF-II they presented an activity similar to COj (Table 2). This enzyme It usually behaves as a marker of oxidative aggression. In a similar result was also observed in the hippocampus in the specific activity of SOD (Table 2) and, indeed, it was able to establish a close direct correlation with the MDA, lipid peroxidation marker (Fig. 2).
Por otra parte, la actividad glutatión peroxidasa fue significativamente reducida en los animales viejos y normalizada en los animales de edad avanzada tratados con IGF-II (Tabla 2).Moreover, glutathione activity peroxidase was significantly reduced in old animals and normalized in elderly animals treated with IGF-II (Table 2).
En el hígado se observó un incremento en la peroxidación lipídica que disminuyó sensiblemente con el tratamiento (Fig. 3A). Sin embargo, no se observaron diferencias entre los tres grupos experimentales en el PCC (nmol/mg de proteína; COj=3.76\pm0.63; V=4.71\pm1.17; V+IGF-II=4.73\pm1.31; Fig. 3B). En cuanto a la actividad específica de enzimas antioxidantes en homogeneizados hepáticos cabe destacar la actividad catalasa: disminuida significativamente en el grupo V y normalizada con el tratamiento (en KU/mg proteína, COj=2.97\pm0.30; V=2.03\pm0.23, p<0.05 vs COj; V+IGF-II=3.00\pm0.44).An increase in the liver was observed in the liver. lipid peroxidation that decreased significantly with the treatment (Fig. 3A). However, no differences were observed. among the three experimental groups in the CCP (nmol / mg of protein; COj = 3.76 ± 0.63; V = 4.71 ± 1.17; V + IGF-II = 4.73 ± 1.31; Fig. 3B). Refering to specific activity of antioxidant enzymes in homogenates hepatic activities include catalase activity: decreased significantly in group V and normalized with treatment (in KU / mg protein, COj = 2.97 ± 0.30; V = 2.03 ± 0.23, p <0.05 vs COj; V + IGF-II = 3.00 ± 0.44).
El estudio por citometria de flujo de mitocondrias hepáticas aisladas, mostró una disminución significativa del PMM en las mitocondrias procedentes de animales viejos con respecto a los COj en todas las condiciones (Fig. 4). Las mitocondrias de animales V+IGF-II mostraron una evidente mejoría en la función mitocondrial, según este parámetro. En la Fig. 5A y B se muestra la disminución del potencial de membrana observado tanto en estadio 4 (con succinato) como en estadio 3 (con la adición de ADP), respectivamente.The flow cytometry study of isolated hepatic mitochondria, showed a decrease Significant PMM in mitochondria from animals old with respect to COJ in all conditions (Fig. 4). Mitochondria of animals V + IGF-II showed a evident improvement in mitochondrial function, according to this parameter. In Fig. 5A and B the decrease in the potential of membrane observed both in stage 4 (with succinate) and in stage 3 (with the addition of ADP), respectively.
Por otra parte, al evaluar el potencial de membrana mitocondrial con oligomicina encontramos unos hallazgos similares (Fig. 5C). En estas condiciones, se mide la magnitud máxima de PMM, porque la oligomicina desactiva de ATPasa y con el ella el bombeo de protones. Por tanto la oligomicina nos permite ensayar las condiciones de máxima negatividad intramitocondrial. En estas condiciones, también encontramos una depleción del PMM en mitocondrias procedentes de animales de edad avanzada (V) y su recuperación en las mitocondrias procedentes del grupo V+IGFII.On the other hand, when evaluating the potential of mitochondrial membrane with oligomycin we found some findings similar (Fig. 5C). Under these conditions, the magnitude is measured maximum of PMM, because the oligomycin deactivates ATPase and with the She pumping protons. Therefore oligomycin allows us test the conditions of maximum intramitochondrial negativity. In these conditions, we also found a depletion of the PMM in mitochondria from elderly animals (V) and their recovery in mitochondria from the V + IGFII group.
Así mismo, la síntesis de ATP (Fig. 6) se encontró reducida en las mitocondrias hepáticas procedentes de animales viejos y alcanzó niveles semejantes a los controles jóvenes en las de animales de 103 semanas tratados con IGF-II a dosis bajas durante un mes. En cuanto a la producción de radicales libres intramitocondriales (Fig. 7), se determinó una producción de ROS significativamente elevada en las mitocondrias del grupo V, mientras que existían concentraciones similares a las de los controles jóvenes (COj) en el grupo V+IGFII.Likewise, the synthesis of ATP (Fig. 6) is found reduced in hepatic mitochondria from old animals and reached levels similar to young controls in those of 103-week-old animals treated with IGF-II at low doses for a month. Refering to intramitochondrial free radical production (Fig. 7), determined a significantly high ROS production in the mitochondria of group V, while concentrations existed similar to those of the young controls (COj) in the group V + IGFII.
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| MATTSON, M.P. et al. Growth Factors Prevent Mitochondrial Dysfunction, Loss of Calcium Hoeostasis, and Cell Injury, but not ATP Depletion in Hippocampal Neurons Deprived of Glucose. Experimental Neurology. 1993. Vol. 121. Núm 1 páginas 1-13. Todo el documento. * |
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