Advances in Depression and Brain-Derived Neurotrophic Factor
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In 2006, Duman et al. proposed “Neurotrophic Theory of Depression” [1]. According to the hypothesis, stress leads to a decrease in the expression of neurotrophic factors such as Brain-derived neurotrophic factor (BDNF) in the limbic structure, and antidepressant therapy can partially reverse the effect caused by stress. The reduction of BDNF and other neurotrophic factors promotes the atrophy of certain brain structures, especially the hippocampus and prefrontal cortex, while antidepressant treatment increases the level of BDNF in the brain, and improves synaptic plasticity and neuronal survival in related brain regions. Neurotrophic factors are a class of molecules that act on the nervous system and play an important role in maintaining cell function. They can regulate the growth, survival, differentiation and cell cycle of nerve cells. There is a hypothesis of neuroendocrine dysfunction in the neurobiochemical mechanism of depression, which is mainly the abnormal activity of the hypothalamic-pituitary-adrenal axis (HPA) and hypothalamic-pituitary-thyroid axis (HPT). This article reviews the related research on depression and brain-derived neurotrophic factors in order to guide clinical research and treatment.Trk receptor
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In 1989 Leitbrock et al. reported the full primary structure of brain-derived neurotrophic factor. The messenger RNA for BDNF was found predominantly in the central nervous system, and the sequence of protein indicated its structural relation to NGF. BDNF belongs to a larger family of neurotrophic molecules. It stimulates the neurite outgrowth and supports neuronal survival.
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Brain-derived neurotrophic factor (BDNF) is a member of neurotrophins family that plays a pivotal role in memory and learning. Brain-derived neurotrophic factor mediates health benefits of physical activity both in humans and animals. The nerve damage and cognitive impairment in diabetic rats are thought to be the result of reduced BDNF levels. The purpose of this study was to examine the effect of short- and long-term moderate forced exercise on BDNF levels in the hippocampus of type 1 diabetic rats.
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Neurotrophins control cell survival. Therefore, we examined whether HIV-1 reduces neurotrophin levels. Serum of HIV-positive individuals exhibited lower concentrations of brain-derived neurotrophic factor (BDNF), but not of other neurotrophins, than HIV-negative individuals. In addition, R5 and X4 strains of HIV-1 decreased BDNF expression in T cells. Our results support the hypothesis that reduced levels of BDNF may be a risk factor for T-cell apoptosis and for neurological complications associated with HIV-1 infection.
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Brain-derived neurotrophic factor (BDNF) is a member of a family of neurotrophins which include nerve growth factor, neurotrophin 3, and neurotrophin 4. Studies over the last three decades have identified mature BDNF as a key regulator of neuronal differentiation, structure, and function; actions mediated by the TrkB receptor. More recently identified isoforms which are translated from the bdnf gene, including the uncleaved precursor, pro-BDNF, and the cleaved prodomain, have been found to elicit opposing functions in neurons through the activation of distinct receptors. This work emphasizes the critical roles for all three isoforms of BDNF in modulating neuronal activity that impact complex human behaviors including memory, anxiety, depression, and hyperphagia.
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Until now neurotrophins like nerve growth factor (NGF), brain-derived neurotrophic factor (BDNA), neurotrophin (NT)-3 and neurotrophic factors like glial-derived neurotrophic factor (GDNF) have been almost exclusively investigated concerning their role in differentiation, growth and survival of specific neurons in the peripheral and central nervous system. However, in the last decade several non-neuronal functions of neurotrophins and neurotrophic factors have been characterized. In the gastrointestinal tract, neurotrophins and neurotrophic factors regulate neuropeptide expression, interact with immunoregulatory cells and epithelial cells and regulate motility during inflammation. This highlights this new and complex regulatory system as important and may lead to new options in the treatment of acute and chronic inflammation of the gut.
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Peripheral nerve injury
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Neurotrophic factors are growth factors or cytokines that are inducible polypeptides and permit intercellular communication. An explosion of information about neurotrophic factors is setting the stage for significant advances in neural disease therapy in the next century. The effects of these trophic factors are overlapping and pleiotropic, acting on many cell types and tissues to control proliferation and differentiation of developing neurons and to exert a variety of functions on mature neurons. Studies of receptors unique to several neurotrophic factor families have revealed exquisite mechanisms of signal transduction. Preclinical trials in neuromuscular disease were promising, but results from initial clinical trials have been disappointing; new and better designed clinical trials are under way. Laboratory investigators also are exploring techniques to deliver factors directly to the central nervous system by means of viral vectors or to exert neurotrophic signals on the nervous system using novel small molecules that stimulate neurotrophic factor or neuroimmunophilin receptors. Combination therapies, refined delivery techniques, and treatment timing may be the key for successful treatment with neurotrophic factors. In this two-part review, we discuss the neurobiology of neurotrophic factors, the characteristics of the major neurotrophic factors, and their therapeutic potential in neuromuscular disease.
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In the developing peripheral nervous system many neurons die shortly after their axons reach their target fields. This loss is thought to match the number of neurons to the size and requirements of their target fields because altering target field size before innervation affects the number of neurons that survive. The neurotrophic hypothesis provides an explanation for how target fields influence the size of the neuronal populations that innervate them. This hypothesis arose from work on nerve growth factor (NGF), the founder member of the neurotrophin family of secreted proteins. Its principal tenet is that the survival of developing neurons depends on the supply of a neurotrophic factor that is synthesized in limiting amounts in their target fields. The neurotrophic hypothesis has, however, been broadened by the demonstration that multiple neurotrophic factors regulate the survival of certain populations of neurons. For example, some neurons depend on several different neurotrophic factors which may act concurrently or sequentially during target field innervation. In addition, there are aspects of neurotrophin action that do not conform with the classic neurotrophic hypothesis. For example, the dependence of some populations of sensory neurons on particular neurotrophins before significant neuronal death takes place raises the possibility that the supply of these neurotrophins is not limiting for survival at this stage of development. There is also evidence that at stages before and after sensory neurons depend on target-derived neurotrophins for survival, neurotrophins act on at least some sensory neurons by an autocrine route. Yet despite the growing wealth of information on the multiple roles and modes of action of neurotrophic factors, the neurotrophic hypothesis has remained the best explanation for how neuronal target fields in the developing peripheral nervous system regulate their innervation density.
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During nervous system development, neurons are generated in numbers exceeding those found in adults. The surplus neurons are eliminated by programmed cell death. In higher organisms this process is influenced by factors outside the cells themselves, called neurotrophic factors. The discovery of neurotrophic factors goes back to the 1950s, when Rita Levi-Montalcini was investigating the relationship between the nervous system and its peripheral targets. She and her collaborators found that on removal of an organ from a chick embryo, its innervating ganglion neurons were lost as well. Conversely, the addition of an extra target resulted in excessive neuronal survival. She postulated that a soluble factor produced by the target promoted neuronal survival. Eventually this factor was isolated and named nerve growth factor (NGF; Cohen & Levi-Montalcini, 1957). A related protein was purified from pig brain in 1982, and was named brain-derived neurotrophic factor (BDNF; Barde et al., 1982). With the discovery of BDNF, a family of neurotrophic factors was established: the NGF family of neurotrophic factors, or the neurotrophins. Since then the mammalian branch of the family has been gifted with two additional members, neurotrophin-3 (NT-3) (Hohn et al., 1990) and NT-4 (Hallbook et al., 1991). To date several proteins with neurotrophic action have been described. Apart from the neurotrophins, members of the glial cell line-derived (GDNF) factor family are the most important.
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