ES2325432B1 - USE OF LOW DOSE OF IGF-I IN AGING FOR ITS NEUROPROTECTORS, ANTIOXIDANTS AND ANABOLIZING EFFECTS. - Google Patents
USE OF LOW DOSE OF IGF-I IN AGING FOR ITS NEUROPROTECTORS, ANTIOXIDANTS AND ANABOLIZING EFFECTS. Download PDFInfo
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- ES2325432B1 ES2325432B1 ES200502798A ES200502798A ES2325432B1 ES 2325432 B1 ES2325432 B1 ES 2325432B1 ES 200502798 A ES200502798 A ES 200502798A ES 200502798 A ES200502798 A ES 200502798A ES 2325432 B1 ES2325432 B1 ES 2325432B1
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Abstract
Utilización de dosis bajas de IGF-I en el envejecimiento por sus efectos neuroprotectores, antioxidantes y anabolizantes.Use of low doses of IGF-I in aging due to its effects neuroprotectors, antioxidants and anabolics.
La presente invención se refiere a la administración de IGF-I en dosis bajas en el envejecimiento por sus efectos neuroprotectores, antioxidantes y anabolizantes, y a su uso en la elaboración de productos con efecto neuroprotector, antioxidante y anabolizante. En particular, la aplicación de la presente invención se refiere a mamíferos, incluyendo obviamente al ser humano. El tratamiento sustitutivo o compensatorio con IGF-I incrementa las concentraciones de testosterona libre y normaliza la capacidad total antioxidante en suero así como el grado de peroxidación lipídica y la actividad específica de la enzima superóxido dismutasa (SOD) en corteza cerebral y en hipocampo. La administración de IGF-I también se observan efectos beneficiosos en hígado en lo que respecta a la peroxidación lipídica, a la actividad de enzimas antioxidantes, y a la función mitocondrialen general.The present invention relates to the administration of IGF-I at low doses in the aging due to its neuroprotective, antioxidant and anabolic agents, and their use in the elaboration of products with effect neuroprotective, antioxidant and anabolic. In particular, the Application of the present invention relates to mammals, obviously including the human being. The substitute treatment or Compensatory with IGF-I increases free testosterone concentrations and normalizes capacity Total serum antioxidant as well as the degree of peroxidation lipid and the specific activity of the superoxide enzyme dismutase (SOD) in cerebral cortex and hippocampus. The administration of IGF-I effects are also observed beneficial in liver with regard to peroxidation lipid, antioxidant enzyme activity, and function general mitochondrialen.
Description
Utilización de dosis bajas de IGF-I en el envejecimiento por sus efectos neuroprotectores, antioxidantes y anabolizantes.Use of low doses of IGF-I in aging due to its effects neuroprotectors, antioxidants and anabolics.
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-I es una hormona peptídica que se sintetiza, sobre todo, en el hígado por el estímulo de la GH. En condiciones fisiológicas, se establece entre la hipófisis y el hígado mecanismos de retracción negativa como los de cualquier glándula endocrina. Ese IGF-I circulante media la mayoría de los efectos sistémicos tradicionalmente atribuidos a la GH (Physiol. Rew., 1990, 70: 591-613).IGF-I is a peptide hormone which is synthesized, above all, in the liver by the stimulation of GH. Under physiological conditions, it is established between the pituitary gland and the liver negative retraction mechanisms like those of any endocrine gland That circulating IGF-I mediates the most of the systemic effects traditionally attributed to the GH (Physiol. Rew., 1990, 70: 591-613).
Esta hormona peptídica de síntesis hepática IGF-I 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). La biodisponibilidad de IGF-I está estrictamente regulada por al menos doce proteínas transportadoras (binding proteins, BP-IGF), que modulan su vida media, biodisponibilidad y accesibilidad a los tejidos (Physiol. Rew., 1990, 70: 591-613; Cytokine Growth Factor Rev., 1997, 8: 45-62).This IGF-I liver synthesis peptide hormone is capable of binding to 4 different receptors (insulin receptor; IGF type I receptor; hybrid IGF receptor and type II IGF receptor). The bioavailability of IGF-I is strictly regulated by at least twelve transport proteins ( binding proteins, BP-IGF ), which modulate their half-life, bioavailability and accessibility to tissues (Physiol. Rew., 1990, 70: 591-613; Cytokine Growth Factor Rev., 1997, 8: 45-62).
Es bien conocido que la deficiencia de insulina constituye la diabetes, o la de hormonas tiroideas el hipotiroidismo, y que el tratamiento sustitutivo resuelve el cuadro clínico. Estas situaciones de deficiencia nos permiten conocer, con matices, los múltiples efectos fisiológicos de cada una de estas hormonas. Es reciente el conocimiento que tenemos de las situaciones de deficiencia de IGF-I, en las cuales el tratamiento sustitutivo podría ser una estrategia terapéutica eficaz.It is well known that insulin deficiency constitutes diabetes, or that of thyroid hormones the hypothyroidism, and that substitute treatment resolves the picture clinical. These deficiency situations allow us to know, with nuances, the multiple physiological effects of each of these hormones The knowledge we have of the IGF-I deficiency situations, in which substitute treatment could be a therapeutic strategy effective.
De las situaciones de deficiencia de IGF-I, la mejor conocida es el Síndrome de Laron o Enanismo de Laron (N. Engl. J. Med., 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 (J. Pediatr. Endocrinol. Metab., 1995, 8: 149-158).Deficiency situations of IGF-I, the best known is Laron Syndrome or Laron's dwarfism (N. Engl. J. Med., 1996, 334: 463-465), characterized by a genetic alteration which determines the absence of receptors for GH in the liver, with the corresponding IGF-I deficiency, while that there are normal or even high levels of GH. Deficiency of IGF-I causes dwarfism and lack of development of these children. Substitute treatment with IGF-I normalizes growth and development (J. Pediatr. Endocrinol. Metab., 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 las muchas proteínas hepáticas que ven comprometida su síntesis en la cirrosis hepática (Clin. Sci. Mol. Med., 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 liver cirrhosis (Clin. Sci. Mol. Med., 1974, 47: 359-366).
Sin embargo, no se estableció que la cirrosis era una situación de "deficiencia de IGF-I" hasta que se vinculó esa deficiente síntesis de IGF-I con la desnutrición progresiva que experimenta el paciente cirrótico. Tras intuir esta relación se caracterizó la cirrosis hepática avanzada como una condición de deficiencia de IGF-I y se propuso la terapia sustitutiva como una estrategia terapéutica. 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; J. Hepatol., 1997, 26: 191-202; J. Hepatol., 1998, 28: 122-131; J. Physiol. Biochem., 2000, 56: 91-99; Hepatology, 2000, 31: 592-600; Liver, 2001, 37: 215-219; Int. J. Biochem. Cell Biol., 2002, 34: 242-252; J. Physiol. Biochem., 2003, 59: 115-118; WJ Gastroenterology, 2004, 10: 2529-2534; BMC Gastroenterology, 2004, 4: 12-20; BMC Gastroenterology, 2005, 5: 7-14; BBA, 2001, 1536: 185-195; J. Hepatol., 2005, 14: 118-125).However, it was not established that cirrhosis it was a situation of "IGF-I deficiency" until that poor synthesis of IGF-I with progressive malnutrition that The cirrhotic patient experiences. After intuiting this relationship, characterized advanced liver cirrhosis as a condition of IGF-I deficiency and therapy was proposed replacement 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; J. Hepatol., 1997, 26: 191-202; J. Hepatol., 1998, 28: 122-131; J. Physiol. Biochem., 2000, 56: 91-99; Hepatology, 2000, 31: 592-600; Liver, 2001, 37: 215-219; Int. J. Biochem. Cell Biol., 2002, 34: 242-252; J. Physiol Biochem., 2003, 59: 115-118; Wj Gastroenterology, 2004, 10: 2529-2534; BMC Gastroenterology, 2004, 4: 12-20; BMC Gastroenterology, 2005, 5: 7-14; BBA, 2001, 1536: 185-195; J. Hepatol., 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. Cabe resaltar que es precisa la adecuada función del 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 otros datos propician abordar una tercera condición de deficiencia de IGF-: 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. It should be noted that it is accurate proper shaft function GH-IGF-I for good condition functional multiple organs and tissues by the effects Anabolic and antioxidants of this liver synthesis hormone. These and other data favor addressing a third condition of IGF- deficiency: aging.
Efectivamente, con la edad el eje GH-IGF-I experimenta un declive (J. Endrocrinol. Invest., 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; 3) Estudios en ratones deficientes en GH ponen de manifiesto una aceleración en el proceso de involución asociado al envejecimiento.Indeed, with age the axis GH-IGF-I experiences a decline (J. Endrocrinol Invest., 2005, 28: 94-98 and 99-108): 1) decreases amplitude, pulse and GH fraction; 2) in parallel, a progressive happens decrease in IGF-I concentrations; 3) Studies in GH-deficient mice show a acceleration in the involution process associated with aging.
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 (Clin. Chem., 1995, 41: 1819-1828).Oxidative stress is a causal mechanism of tissue aging and cell death (Clin. Chem., 1995, 41: 1819-1828).
- \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
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Por otra parte, la amplia difusión de receptores para IGF-I en el cerebro y en la médula espinal permiten suponer que estos efectos pudieran ser similares en el SNC (Endocrinology, 1988, 1123: 2089-99). Además, existen antecedentes demostrando efectos neuroprotectores y neurotróficos de esta hormona (Brain Res., 2003, 991: 34-45; Prog. Neurobiol., 2003, 70: 443-462 Brain Res. Mol. Brain Res., 2004, 131: 33-50; Neuroreport, 2004, 15: 2251-4; Brain Res., 2004, 1009: 213-218; Eur. J. Pharmacol., 2004, 490: 25-31; J. Neurosci. Res., 2004, 76: 98-103; Eur. J. Neurosci., 2005, 21: 1489-1502).Moreover, the wide diffusion of receivers for IGF-I in the brain and spinal cord allow us to assume that these effects could be similar in the CNS (Endocrinology, 1988, 1123: 2089-99). Further, there is a history demonstrating neuroprotective effects and neurotrophic of this hormone (Brain Res., 2003, 991: 34-45; Prog. Neurobiol., 2003, 70: 443-462 Brain Res. Mol. Brain Res., 2004, 131: 33-50; Neuroreport, 2004, 15: 2251-4; Brain Res., 2004, 1009: 213-218; Eur. J. Pharmacol., 2004, 490: 25-31; J. Neurosci. Res., 2004, 76: 98-103; Eur. J. Neurosci., 2005, 21: 1489-1502).
Una revisión extensa de la bibliografía pone de manifiesto cierta polémica en lo que respecta a la implicación de IGF-I en el envejecimiento (Mech. Ageing Dev., 2004, 125: 397-403; Mech. Ageing Dev., 2005, 126:305-307; Endocrinology, 2005, 146: 2920-2932). Aunque en los últimos años se ha incrementado la proporción de publicaciones que sugieren que los mecanismos genéticos y endocrinos identificados y bastante estudiados en roedores, incluyendo el papel de IGF-I, pueden ser similares a los de otras especies de mamíferos, incluyendo al ser humano (Horm. Res., 2004, 62: 104-109; Cell. Mol. Life Sci., 2005, 62: 320-343; Endocrinology, 2005, 146: 3718-3723), aún no se ha reconciliado la importancia de IGF-I, sobre todo en lo que se refiere al desarrollo, funcionamiento y mantenimiento del sistema nervioso central (Neurobiol. Aging, 2003, 24: 573-581; Growth Horm. IGF Res., 2004, 14: S39-S43; Neurobiol. Aging, 2005, 26: 929-937; Cereb. Cortex, 2005, 15: 571-577) con el efecto observado en roedores transgénicos o mutantes sobre la longevidad, en los que la disrupción de la señalización vía IGF-I condiciona una mayor longevidad (Trends Genet., 2002, 18: 295-231; Nature, 2003, 421: 182-187; Biogerontology, 2003, 4: 1-8). No obstante, diversos autores critican el uso de dichos modelos genéticamente alterados basándose en que los mismos presentan múltiples deficiencias endocrinas adicionales e incluso anomalías en el desarrollo (J. Gerontol. B–Biol., 2002, B177-B188; Trends Genet., 2002, 18: 295-301; Biogerontology, 2003, 4: 1-8). La presente invención demuestra, usando como modelo roedores no modificados genéticamente, que la administración de IGF-I en dosis bajas a mamíferos adultos que muestran síntomas característicos de envejecimiento induce efectos beneficiosos que difícilmente pueden promover una aceleración en el proceso de envejecimiento.An extensive review of the bibliography puts I manifest a certain controversy regarding the implication of IGF-I in aging (Mech. Ageing Dev., 2004, 125: 397-403; Mech Ageing Dev., 2005, 126: 305-307; Endocrinology, 2005, 146: 2920-2932). Although in recent years it has increased the proportion of publications that suggest that genetic and endocrine mechanisms identified and quite studied in rodents, including the role of IGF-I, may be similar to those of other species of mammals, including humans (Horm. Res., 2004, 62: 104-109; Cell Mol. Life Sci., 2005, 62: 320-343; Endocrinology, 2005, 146: 3718-3723), the importance has not yet been reconciled of IGF-I, especially as regards development, functioning and maintenance of the nervous system central (Neurobiol. Aging, 2003, 24: 573-581; Growth Horm IGF Res., 2004, 14: S39-S43; Neurobiol Aging, 2005, 26: 929-937; Cereb Cortex, 2005, 15: 571-577) with the effect observed in rodents transgenic or mutants on longevity, in which the signal disruption via IGF-I conditions greater longevity (Trends Genet., 2002, 18: 295-231; Nature, 2003, 421: 182-187; Biogerontology, 2003, 4: 1-8). However, Several authors criticize the use of these genetically modified models. altered based on the fact that they have multiple additional endocrine deficiencies and even abnormalities in the development (J. Gerontol. B – Biol., 2002, B177-B188; Trends Genet., 2002, 18: 295-301; Biogerontology, 2003, 4: 1-8). The present invention demonstrates, using as a model non-genetically modified rodents, that the administration of IGF-I in low doses to mammals adults showing characteristic symptoms of aging induces beneficial effects that can hardly promote a acceleration in the aging process.
En lo que respecta a la literatura "patente", existen múltiples documentos en los que se comentan efectos beneficiosos de IGF-I y en los que se reivindica el uso de dicha hormona, en general o de alguna de sus isoformas, para el tratamiento de de pérdida de masa muscular (por ejemplo WO8803409, WO9401101, WO9910013), de afecciones cardiacas (por ejemplo WO03066082), y principalmente de desórdenes neuronales (por ejemplo WO9014838, WO9308826, WO9302695, WO9801128, WO0136483). Sin embargo, son escasos los documentos en los que se relaciona IGF-I y envejecimiento (por ejemplo WO9401101, WO03000861, WO2004085996), y, aunque en algunos (EP1349559, WO2005039546) de ellos se aborda un objetivo que puede entenderse próximo al descrito en la presente invención, la forma de hacerlo es diferente: por ejemplo, mientras que en el documento WO2005039546 se administran compuestos que inciden en los niveles de IGF-I, en la presente invención se refiere la administración directa de IGF-I, evitando efectos colaterales que pueda tener la administración de precursores o inductores.In regards to literature "patent", there are multiple documents in which they are commented beneficial effects of IGF-I and where vindicates the use of said hormone, in general or of any of its isoforms, for the treatment of loss of muscle mass (by example WO8803409, WO9401101, WO9910013), of heart conditions (for example WO03066082), and mainly of neuronal disorders (for example WO9014838, WO9308826, WO9302695, WO9801128, WO0136483). However, there are few documents in which relates IGF-I and aging (for example WO9401101, WO03000861, WO2004085996), and, although in some (EP1349559, WO2005039546) of them addresses an objective that can understood as described in the present invention, the form doing so is different: for example, while in the document WO2005039546 compounds that affect the levels of IGF-I, in the present invention the direct administration of IGF-I, avoiding effects collateral that precursor administration may have or inductors
La presente invención se refiere a la administración del factor de crecimiento semejante a la insulina tipo I (IGF-I) en dosis bajas en el envejecimiento por sus efectos neuroprotectores, antioxidantes y anabolizantes. En particular, se refiere a la administración de una cantidad terapéuticamente efectiva de IGF-I. Dicha administración comprende la administración vía oral, percutánea, subcutánea, intramuscular, intraarticular, o intravenosa. En el caso de administración vía oral, se contempla la posibilidad de hacerlo a través de alimentos enriquecidos, por ejemplo, leche natural, leche artificial, o calostro (calostrum).The present invention relates to the administration of insulin-like growth factor type I (IGF-I) in low doses in aging for its neuroprotective, antioxidant and anabolic effects. In particular, it refers to the administration of a therapeutically effective amount of IGF-I. Said administration comprises administration orally, percutaneously, subcutaneously, intramuscularly, intraarticularly, or intravenously. In the case of oral administration, the possibility of doing so through enriched foods is contemplated, for example, natural milk, artificial milk, or colostrum ( calostrum ).
La presente invención también se refiere al uso de IGF-I en la elaboración de productos con efecto neuroprotector, antioxidante y anabolizante. En particular, se refiere a su uso en la elaboración de productos que sean medicamentos o composiciones farmacéuticas que comprendan una cantidad terapéuticamente efectiva de IGF-I. En lo que a la administración de dicho producto en cuya elaboración se emplea IGF-I, la administración puede ser por vía oral, percutánmea, subcutánea, intramuscular, intraarticular, o intravenosa.The present invention also relates to the use of IGF-I in the elaboration of products with effect neuroprotective, antioxidant and anabolic. In particular, it refers to its use in the elaboration of products that are medications or pharmaceutical compositions that comprise a therapeutically effective amount of IGF-I. In that the administration of said product in whose elaboration is employs IGF-I, administration can be via oral, percutaneous, subcutaneous, intramuscular, intraarticular, or intravenous
En particular, la aplicación de la presente invención se refiere a mamíferos, incluyendo obviamente al ser humano. 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-I incrementa las concentraciones de testosterona libre y normaliza la capacidad total antioxidante en suero así como el grado de peroxidación lipídica y la actividad específica de la enzima superóxido dismutasa (SOD) en corteza cerebral y en hipocampo. La administración de IGF-I también se observan efectos beneficiosos en hígado en lo que respecta a la peroxidación lipídica, a la actividad de enzimas antioxidantes, y a la función mitocondrial en general.In particular, the application of this invention refers to mammals, obviously including being human. In aging the hormone deficiency can be seen IGF-I and antioxidant capacity while a significant increase in blood glucose, cholesterolemia, lipid peroxidation, as well as in the concentrations of triglycerides Substitute or compensatory treatment with IGF-I increases the concentrations of Free testosterone and normalizes the total antioxidant capacity in serum as well as the degree of lipid peroxidation and activity Specific enzyme superoxide dismutase (SOD) in bark cerebral and hippocampus. The administration of IGF-I beneficial effects on liver are also observed in what regards lipid peroxidation, enzyme activity antioxidants, and mitochondrial function in general.
En resumen, la administración de IGF-I, a dosis bajas, induce efectos antioxidantes, neuroprotectores y hepatoprotectores, mejorando la función mitocondrial.In short, the administration of IGF-I, 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-I (V+IGF-I) y tratados con solución salina (V). XE\pmSM; *p<0.05 vs COj; ***p<0.001 vs COj; ^{#}p<0.05 vs V.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-I (V + IGF-I) and treated with saline solution (V). XE ± SM; * p <0.05 vs COj; *** p <0.001 vs COj; # p <0.05 vs. V.
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-I (V+IGF-I) 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-I (V + IGF-I) 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.
Tabla 3. Actividad específica de enzimas antioxidantes en homogeneizados hepáticos, incluyendo catalasa, superóxido dismutasa (SOD) y Glutatión peroxidasa (GPX); en animales jóvenes (COj), animales viejos tratados con IGF-I (V+IGF-I) y tratados con solución salina (V). X\pmESM; *p<0.05 vs COj.Table 3. Specific enzyme activity antioxidants in liver homogenates, including catalase, superoxide dismutase (SOD) and Glutathione peroxidase (GPX); in animals young (COj), old animals treated with IGF-I (V + IGF-I) and treated with saline (V). X ± ESM; * p <0.05 vs COj.
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-I (V+IGF-I) y tratados con solución salina (V). (A) X \pm ESM; *p<0,05 vs COj; ^{&}p<0,05 vs V; (B) X \pm ESM; *p<0,05 vs COj; ^{&}p<0,05 vs V; (C) X \pm ESM; **p<0,01 vs COj; y (D) X f 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-I (V + IGF-I) and treated with saline (V). (A) X ± ESM; * p <0.05 vs COj; & p <0.05 vs V; (B) X \ pm ESM; * p <0.05 vs COj; & p <0.05 vs V; (C) X ± ESM; ** p <0.01 vs COj; and (D) X f ESM; * p <0.05 vs COj.
Figura 2. Correlación directa y significativa entre la actividad específica de la enzima superóxido dismutasa (SOD) con el marcador de peroxidación lipídica MDA.Figure 2. Direct and significant correlation between the specific activity of the enzyme superoxide dismutase (SOD) with the MDA lipid peroxidation marker.
Figura 3. Daño oxidativo, en función de la peroxidación lipíca, en tejido hepático. X \pm ESM; ***p<0,001 vs COj; ^{&&}p<0,01 vs V.Figure 3. Oxidative damage, as a function of lipid peroxidation, in liver tissue. X ± ESM; *** p <0.001 vs COj; ^ && p <0.01 vs. V.
Figura 4. Potencial de membrana mitocondrial, evaluado por citometría de flujo con rodamina 123, en mitocondrias aisladas en animales jóvenes (COj), animales viejos tratados con IGF-I (V+IGF-I) 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-I (V + IGF-I) 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-I (V+IGF-I) y tratados con solución salina (V), según las diferentes condiciones: (A) Estado 4 (X \pm ESM **p<0,01 V vs Controles jóvenes; ^{&}p<0,05 V+IGF-I vs V; p=ns COj vs V+IGF-I), (B) Estado 3 (X \pm ESM; **p<0,01 V vs COj; ^{&}p<0,05 V+IGF-I vs V; p=ns COj vs V+IGF-I), y (C) con oligomicina (X \pm ESM; *p<0,05 V vs Controles jóvenes; ^{&}p<0,05 V+IGF-I vs V; p=ns COj vs V+IGF-I).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-I (V + IGF-I) and treated with saline solution (V), according to the different conditions: (A) State 4 (X ± ESM ** p <0.01 V vs Young Controls; & p <0.05 V + IGF-I vs V; p = ns COj vs V + IGF-I), (B) State 3 (X ± ESM; ** p <0.01 V vs COj; & p <0.05 V + IGF-I vs V; p = ns COj vs V + IGF-I), and (C) with oligomycin (X ± ESM; * p <0.05 V vs Young controls; & p <0.05 V + IGF-I vs V; p = ns COj vs V + IGF-I).
Figura 6. Síntesis de ATP en animales jóvenes (COj), animales viejos tratados con IGF-I (V+IGF-I) 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-I (V + IGF-I) 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 COj; ^{&&}p<0,01 V+IGF-I vs V; p=ns COj vs V+IGF-I.Figure 7. Intramitochondrial production of free radicals (hydrogen peroxide). X ± ESM; *** p <0.001 V vs COj; && p <0.01 V + IGF-I vs V; p = ns COj vs V + IGF-I.
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A continuación se describe un estudio del efecto del tratamiento con IGF-I 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-I 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.
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-I 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-I 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-I a dosis de 2 \mug por 100 g de peso corporal y por día durante 31 días (V+IGF-I); 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-I at a dose of 2 µg per 100 g of body weight and per day for 31 days (V + IGF-I); and the other 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-I) se estudiaron los siguientes parámetros, en homogeneizados de cerebro (corteza e hipocampo) y hepáticos: 1) el grado de peroxidación lipídica: Maloldialdehido (Clin. Chem., 1995, 41: 1819-1828: 79; Gastroenterology, 1997, 113: 1682-1691); 2) el grado de carboxilación de proteínas (Protein carboxil content o PCC) (Clin. Chem., 1995, 41: 1819-1828: 79); y 3) la actividad específica de las principales enzimas antioxidantes (Clin. Chem., 1995, 41: 1819-1828: 79; Gastroenterology, 1997, 113: 1682-1691): superóxido dismutasa (SOD), catalasa y Glutatión peroxidasa (GSHPx).To evaluate the oxidative damage and antioxidant defenses of old animals (treated and untreated with IGF-I) the following parameters were studied, in brain homogenates (cortex and hippocampus) and liver: 1) the degree of lipid peroxidation: Maloldialdehyde (Clin. Chem., 1995, 41: 1819-1828: 79; Gastroenterology, 1997, 113: 1682-1691); 2) the degree of carboxylation of proteins ( Protein carboxy content or PCC) (Clin. Chem., 1995, 41: 1819-1828: 79); and 3) the specific activity of the main antioxidant enzymes (Clin. Chem., 1995, 41: 1819-1828: 79; Gastroenterology, 1997, 113: 1682-1691): superoxide dismutase (SOD), catalase and Glutathione peroxidase (GSHPx ).
La función mitocondrial fue evaluada por citometría de flujo (EPICS XL, Coulter) tal y como se describe en trabajos previos (Clin. Chem., 1995, 41: 1819-1828: 79; 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 (Clin. Chem., 1995, 41: 1819-1828: 79; Gastroenterology, 1997, 113: 1682-1691). Be determined: 1) the mitochondrial membrane potential (PMM), with the different substrates, in the presence of fluorochrome rhodamine 123 (Rh123); 2) Synthesis of ATP; 3) Free radical production intramitochondrial (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 (Clin. Chem., 1995, 41: 1819-1828: 79; Gastroenterology, 1997, 113: 1682-1691; J. Physiol. Biochem., 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 (Clin. Chem., 1995, 41: 1819-1828: 79; Gastroenterology, 1997, 113: 1682-1691; J. Physiol. Biochem., 2003, 59: 115-118).
El tratamiento con dosis tan bajas como 2 \mug por 100 g de pc fue capaz de incrementar significativamente las concentraciones circulantes de IGF-I (en ng/mL, COj=1030\pm67.01; V=662\pm17.43, p<0.05; V+IGF-I=958\pm84.91, p<0.05 vs COj y V).Treatment with doses as low as 2 \ mug per 100 g of pc was able to significantly increase the circulating concentrations of IGF-I (in ng / mL, COj = 1030 ± 67.01; V = 662 ± 17.43, p <0.05; V + IGF-I = 958 ± 84.91, p <0.05 vs COj and V).
Los animales viejos (V) mostraban un aumento significativo de la glucemia, colesterolemia y las concentraciones de triglicéridos (Tabla 1). El tratamiento sustitutivo normalizó la glucemia y redujo los triglicéridos (grupo V+IGF-I). Además el tratamiento incrementó las concentraciones de testosterona libre (en pg/mL, COj=7.35\pm2.91; V=4.01\pm0.68; 11.86\pm3.08, p<0.05 vs V).Old animals (V) showed an increase Significant glycemia, cholesterolemia and concentrations of triglycerides (Table 1). The replacement treatment normalized the glycemia and reduced triglycerides (group V + IGF-I). In addition the treatment increased the concentrations of free testosterone (in pg / mL, COj = 7.35 ± 2.91; V = 4.01 ± 0.68; 11.86 ± 3.08, p <0.05 vs V).
Por otra parte, la administración de IGF-I normalizó 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; V+IGF- I=0.88\pm0.02, p<0.01).Moreover, the administration of IGF-I normalized the total antioxidant capacity in serum that was significantly reduced in old animals with respect to young controls (in mmol / L, COj = 0.91- ± 0.01; V = 0.84 ± 0.01, p <0.001; V + IGF- I = 0.88 ± 0.02, p <0.01).
El grado de peroxidación lipídica (estimado por las concentraciones de MDA), así como el Protein Carboxil Conten (PCC) (Figura 1), estaban significativamente elevados, tanto en corteza como en hipocampo, en los animales viejos y el tratamiento fue capaz de normalizarlos.The degree of lipid peroxidation (estimated by the concentrations of MDA), as well as the Protein Carboxil Conten (PCC) (Figure 1), were significantly elevated, both in bark and hippocampus, in old animals and the 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-I 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 encontró 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-I they presented an activity similar to COj (Table 2). This enzyme It usually behaves as a marker of oxidative aggression. In homogenized hippocampus also found a result similar in the specific activity of SOD (Table 2), and indeed, a close direct correlation could be established with the MDA, lipid peroxidation marker (Fig. 2).
Por otra parte, la actividad Glutatión peroxidasa se encontró significativamente reducida en los animales viejos y normalizada en los animales de edad avanzada tratados con IGF-I (V+IGF-I) (Tabla 2).On the other hand, Glutathione activity peroxidase was found significantly reduced in animals old and normalized in elderly animals treated with IGF-I (V + IGF-I) (Table 2).
En el hígado se observó un incremento en la peroxidación lipídica que disminuyó sensiblemente con el tratamiento (Fig. 3). 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-I=4.73\pm1.31). En la actividad específica de enzimas antioxidantes en homegeneizados hepáticos (Tabla 3) cabe destacar la actividad catalana: disminuida significativa en el grupo V y normalizada con el tratamiento (grupo V+IGF) (en KU/mg proteína, COj=2.97\pm0.30; V=2.03\pm0.23, p<0.05 vs COj; V+IGF-I=3.00\pm0.44).An increase in the liver was observed in the liver. lipid peroxidation that decreased significantly with the treatment (Fig. 3). 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-I = 4.73 ± 1.31). In the specific activity of antioxidant enzymes in liver homegeneized (Table 3) fits highlight the Catalan activity: significant decrease in the group V and normalized with treatment (group V + IGF) (in KU / mg protein, COj = 2.97 ± 0.30; V = 2.03 ± 0.23, p <0.05 vs COj; V + IGF-I = 3.00 ± 0.44).
En el estudio por citometría 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). Mientras, las mitocondrias de animales V+IGF-I mostraron una evidente mejoría en la función mitocondrial, según este parámetro (Figura 5).In the study by flow cytometry of isolated hepatic mitochondria, showed a decrease Significant PMM in mitochondria from animals old with respect to COJ, in all conditions (Fig. 4). Meanwhile, the mitochondria of animals V + IGF-I showed an evident improvement in mitochondrial function, according to this parameter (Figure 5).
Así mismo, la síntesis de ATP (Figura 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-I a dosis bajas durante un mes. En cuanto a la producción de radicales libres intramitocondriales (Figura 7), se encontró 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+IGF.Likewise, the synthesis of ATP (Figure 6) is found reduced in hepatic mitochondria from old animals and reached levels similar to controls young people in 103-week-old animals treated with IGF-I at low doses for a month. Refering to intramitochondrial free radical production (Figure 7), found 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 + IGF.
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| CARTER, W.J. "{}Effect of anabolic hormones and insulin-like growth factor-I on muscle mass and strength in elderly persons"{}. CLINICS IN GERIATRIC MEDICINE. 01.11.1995; Vol. 11, n$^{o}$. 4, páginas 735-748; todo el documento, especialmente páginas 740-742. * |
| GARCÍA-FERNÁNDEZ, M. et al. "{}Antioxidant effects of insulin-like growth factor-I (IGF-I) in rats with advanced liver cirrhosis"{}. BMC GASTROENTEROLOGY. 03.03.2005. Vol 5:7, todo el documento. * |
| SONNTAG, W.E. et al. "{}The effects of growth hormone and IGF-I deficiency on cerebrovascular and brain ageing"{}. JOURNAL OF ANATOMY. 01.11.2000. Vol 197, Pt 4, páginas 575-585; todo el documento. * |
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