Control de la neurotraducción hipotalámica por los neurotransmisores cerebrales : regulación de la somastostatina hipotalámica por las catecolaminas

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Biológicas, leída en 1982.Fac. de Ciencias BiológicasTRUEProQuestpu

Homeostasis cerebral e IGF-I

Aunque los IGFs, y mas concretamente el IGF-I son conocidos sobretodo por su implicación fundamental en el eje somato-trópico controlado por la hormona de crecimiento hipofisaria, en los últimos años se ha ido desvelando un papel también muy importante del IGF-I a nivel cerebral. Quizás lo más llamativo de este nuevo aspecto de la fisiología del IGF-I es que sea el IGF-I circulante, de procedencia mayoritariamente hepática, el que tenga un efecto neuroactivo. Si bien el cerebro adulto produce pequeñas cantidades de IGF-I, es el de origen periférico el que resulta esencial para un funcionamiento adecuado de este órgano. De hecho, el papel del IGF-I cerebral en la fisiología neural todavía no está claro, revelando su importancia al parecer sólo en condiciones de alteración de la homeostasis. Sin embargo, la ausencia de IGF-I circulante genera un enorme impacto neurológico, produciendo desordenes anatómicos, bioquímicos y conductuales. Quizás lo mas llamativo del IGF-I sérico sea su papel sobre funciones cerebrales superiores tales como el aprendizaje y la memoria. Esta conexión entre periferia y sistema nervioso central implica el paso del IGF-I circulante al cerebro a través de las barreras hemato-encefálicas, hecho conocido desde hace años pero aún no aceptado plenamente ya que se considera que estas barreras son impermeables a la mayor parte de las proteínas sanguíneas. El IGF-I es un cito-protector de amplio espectro, también en el cerebro. Es además esencial para el mantenimiento tisular, encargándose de mantener una población celular acorde a las demandas funcionales. Contribuye al soporte energético celular de dos maneras, manteniendo el árbol vascular cerebral y por lo tanto asegurando un aporte de oxígeno y nutrientes, y regulando el metabolismo celular como agente anabólico por excelencia. Además ejerce funciones mas específicas del tejido neural. En concreto regula la excitabilidad neural –modula una enorme diversidad de canales iónicos, y diversos sistemas de neurotransmisión. De esta forma contribuye directamente al mantenimiento de las funciones superiores cerebrales que se traducen en una influencia directa sobre las capacidades cognitivas. Pero si algo define la neurobiología de este factor tan pleiotrópico es su papel central en la homeostasis cerebral. Es por eso que cualquier enfermedad neurológica presenta alteraciones en el sistema IGF-I. En situaciones de alteración de la homeostasis siempre se da una respuesta reactiva no sólo del IGF-I, también de otros muchos factores neuroprotectores. Pero es el IGF-I el encargado de orquestar en gran medida la respuesta adaptativa. De esta manera el IGF-I se puede considerar un elemento maestro en la homeostasis cerebral.

Brain IGF-I regulates hippocampal neurogenesis, synaptic plasticity, and sexual dimorphic behaviour

Comunicación presentada a SSii 2022 Spanish Symposium on IGFs and Insulin 2022: Implications in Physiology and DiseaseInsulin-like growth factor-I (IGF-I) exerts multiple actions, regulating body growth, cell proliferation, adult neurogenesis, neuronal and glial differentiation, synaptic plasticity and behaviour, among other processes. Both circulating and locally synthesized IGF-I are active, although the role of IGF-I from different sources is poorly understood. We previously found that brain IGF-I plays a major role in promoting the correct generation, migration and maturation of neurons from neural stem cells during postnatal adult hippocampal neurogenesis (Nieto-Estévez et al., 2016), although electrophysiological or behavioural phenotypes were not investigated in that study. Here we show that the lack of brain IGF-I almost completely abrogates hippocampal LTP, as well as altering sex-dependent behaviour and causing major changes in the hippocampal proteome. We suggest that the disruptions to the hippocampal proteome of conditional knockout Igf-I mice may partially underlie the changes observed in synaptic plasticity and behaviour

Circulating insulin-like growth factor I and cognitive function: Neuromodulation throughout the lifespan

Insulin-like growth factor I (IGF-I) is central to the somatotropic (growth hormone) axis. It promotes tissue growth and continues to have anabolic effects in adulthood. Accumulating evidence from the last decade, however, reveals that circulating levels of IGF-I also significantly affects cognitive brain function. Specifically, the decline of serum IGF-I might be associated with the age-related cognitive decline in elderly people. Moreover, psychiatric and neurological conditions characterized by cognitive impairment may be characterized by altered levels of IGF-I. Some evidence is emerging that interventions that target the GH/IGF-I axis may improve cognitive functioning, at least in deficient states. As there is evidence linking high serum IGF-I levels with cancer risk, these interventions should be carefully evaluated. On a cellular and molecular level, IGF-I may be a crucial component of neural homeostasis since disturbed IGF-I input is inevitably linked to perturbed function. Consistent with this, all nerve cells are potential targets of IGF-I actions, including neurons, glia, endothelial, epithelial, and perivascular cells. Indeed, many key cellular processes in the brain are affected by IGF-I's neurotrophic and modulatory actions. We review the regulation by IGF-I of neurotransmission and neuronal plasticity and conclude that serum IGF-I is an important mediator of neuronal growth, survival and function throughout the lifespan. The role of IGF-I in synaptic plasticity render its neurotrophic potential a key target for remediating the cognitive impairment associated with a range of neurological conditions. © 2009 Elsevier Ltd. All rights reserved.Peer Reviewe

Toward a comprehensive neurobiology of IGF-I

Insulin-like growth factor I (IGF-I) belongs to an ancient family of hormones already present in early invertebrates. The insulin family is well characterized in mammals, although new members have been described recently. Since its characterization over 50 years ago, IGF-I has been considered a peptide mostly involved in the control of body growth and tissue remodeling. Currently, its most prominent recognized role is as a quasi-universal cytoprotectant. This role connects IGF-I with regulation of lifespan and with cancer, two areas of very active research in relation to this peptide. In the brain, IGF-I was formerly considered a neurotrophic factor involved in brain growth, as many other neurotrophic factors. Other aspects of the neurobiology of IGF-I are gradually emerging and suggest that this growth factor has a prominent role in brain function as a whole. During development IGF-I is abundantly expressed in many areas, whereas once the brain is formed its expression is restricted to a few regions and in very low quantities. However, the adult brain appears to have an external input from serum IGF-I, where this anabolic peptide is abundant. Thus, serum IGF-I has been proven to be an important modulator of brain activity, including higher functions such as cognition. Many of these functions can be ascribed to its tissue-remodeling activity as IGF-I modulates adult neurogenesis and angiogenesis. Other activities are cytoprotective; indeed, IGF-I can be considered a key neuroprotective peptide. Still others pertain to the functional characteristics of brain cells, such as cell excitability. Through modulation of membrane channels and neurotransmission, IGF-I impinges directly on neuronal plasticity, the cellular substrate of cognition. However, to fully understand the role of IGF-I in the brain, we have to sum the actions of locally produced IGF-I to those of serum IGF-I, and this is still pending. Thus, an integrated view of the role played by IGF-I in the brain is not yet possible. An operational approach to overcome this limitation would be to consider IGF-I as a signal coupling environmental influences on body metabolism with brain function. Or in a more colloquial way, we may say that IGF-I links body >fitness> with brain fitness, providing a mechanism to the roman saying >mens sana in corpore sano>. © 2010 Wiley Periodicals, Inc.Peer Reviewe

Targeting insulin-like growth factor-1 to treat Alzheimer's disease

The 'amyloid cascade hypothesis' proposes that disturbances in amyloid metabolism cause Alzheimer's disease (AD). However, a comprehensive explanation of the mechanisms leading to brain amyloidosis is still pending. Building on previous findings with insulin, and recent observations with insulin-like growth factor-1 (IGF-1) in AD pathology, new evidence suggests that the interaction of environmental factors and inheritance lead to abnormally reduced input/traffic of serum IGF-1 at the blood-brain barriers. The resultant deterioration in brain IGF-1 function may originate all the pathological changes observed in late-onset AD. These include cognitive loss, abnormal amyloid metabolism and aberrant Tau phosphorylation, as well as disturbances, such as inflammation, oxidative stress or mitochondrial dysfunction, among others. A better understanding of the role of IGF-1 in all these perturbations is required, particularly in relation to cognition. Furthermore, insight into the environmental factors contributing to abnormally reduced IGF-1 function in AD brains may become crucial in development of much needed disease-modifying strategies. © 2007 Informa UK Ltd.Peer Reviewe

Serum growth factors and neuroprotective surveillance: Focus on IGF-I

The adult brain requires a constant trophic input for appropriate function. Although the main source of trophic factors for mature neurons is considered to arise locally from glial cells and synaptic partners, recent evidence suggests that hormonal-like influences from distant sources may also be important. These include not only relatively well-characterized steroid hormones that cross the brain barriers, but also blood-borne protein growth factors able to cross the barriers and exert unexpected, albeit specific, trophic actions in diverse brain areas. Insulin-like growth factor I (IGF-I) is until now the serum neurotrophic factor whose actions on the adult brain are best-characterized. This is because IGF-I has been known for many years to be present in serum, whereas the presence in the circulation of other more classical neurotrophic factors has only recently been recognized. Thus, new evidence strongly suggests that IGF-I, and other blood-borne neurotrophic factors such as Fibroblast Growth Factor (FGF-2) or the neurotrophins, exert a tonic trophic input on brain cells, providing a mechanism for what we may refer to as neuroprotective surveillance. Protective surveillance includes >first-line> defense mechanisms ranging from blockade of neuronal death after a wide variety of cellular insults to upregulation of neurogenesis when defenses against neuronal death are overcome. Most importantly, surveillance should also encompass modulation of homeostatic mechanisms to prevent neuronal derangement. These will include modulation of basic cellular processes such as metabolic demands and maintainance of cell-membrane potential as well as more complex processes such as regulation of neuronal plasticity to keep neurons able to respond to constantly changing functional demands.Peer Reviewe