Various approaches to overcome this problem include neurotrophic factor delivery by special devices and gene therapy. A "trophic factor" can be generally defined as any molecule that supports the survival of cells.
Nerve growth factors are polypeptides that regulate the proliferation, survival, migration, and differentiation of cells in the nervous system. Most of the studies have focused on the effect of growth factors on neuronal survival and maintenance, hence, the term "neurotrophic factors. It is bound to specific receptors, then internalized and transported by retrograde axonal transport to the cell soma where multiple survival-promoting effects are initiated.
Neurotrophic factors act via 2 different classes of receptors and activation of various signaling pathways in the target cells Machalinski et al The study of these factors began in the s; 2 decades later, a target-derived soluble protein was shown to influence neuronal survival and was termed "nerve growth factor" Levi-Montalcini and Hamburger Nerve growth factor provided the first molecular basis for the concept of neurotrophic signaling between neurons and their targets; however, recognition of the therapeutic potential of nerve growth factor did not take place until the s Cohen Another 2 decades passed before the discovery of further nerve growth factors in the s.
These discoveries included isolation of brain-derived neurotrophic factor Barde et al , localization of fibroblast growth factor in neurons of the brain Pettmann et al , and cloning of brain-derived neurotrophic factor Leibrock et al Other discoveries in this area include cloning of human ciliary neurotrophic factor Lam et al and isolation of rat glial cell line-derived neurotrophic factor Lin et al Growth factors, termed "cytokines," have also been found to modulate neuronal processes and are sometimes referred to as neuropoietic cytokines or, simply, neurokines. Originally, cytokines were thought to be derived solely from the cells of the immune system, but now they are known to be produced by the cells of the central nervous system also.
In this article, the term "neurotrophic factors" will be used in a broad sense to cover all neurotrophins nerve growth factor and brain-derived neurotrophic factor , growth factors, and other substances that promote survival and repair of the cells of the nervous system. All NTFs can bind to the p75 receptor. Although both the Trk receptor and the p75NTR receptor have a ligand-binding region and a cytoplasmic region, the sequences of the two have no similarities.
After NTF dimerization, it binds to the Trk receptor, dimerizing the receptor and activating the catalytic tyrosine protein kinase region. The dimerized Trk receptor auto phosphorylates several signaling pathways within the cell. These are tyrosine phosphorylated after recognition of a specific ligand at a recognition site, and they contain a phosphoserine-binding motif such as Src homology region 2 SH2.
The SH2 binding protein linkage activates the Trk receptor to achieve its neurotrophic activity primarily through two distinct intracellular signaling pathways. The major neuronal survival pathways, including the SH2-linked Trk receptor, activate PI3K kinase, increase its phosphorylation level, and then sequentially activate downstream Akts that have multiple functions in the apoptotic program. CREB proteins play multiple roles in cell cycle, neurite outgrowth, and synaptic plasticity.
Neurotrophic factors and their effects in the treatment of multiple sclerosis
Activation of the Trk receptor can further activate multiple downstream pathways. And it interacts with Trk receptors to enhance the recognition of different neurotrophic factors. There is extensive programmed cell death during the development of the nervous system, which determines the number of cells and the correct distribution of neurons during development. NTF is highly expressed early in development and is essential for neuronal survival and selection at different developmental stages.
The neurotrophic hypothesis provides a functional analysis of the role of NTF in the development of the nervous system.
Neurotrophic Factors and Regeneration
The nervous system shapes itself to maintain the most competitive and appropriate synaptic connections. A small amount of NTF produced by neurons compressing target cells indicates selective cell survival. In the central nervous system, repeated expression of multiple NTF receptors and cognate ligands allows for a variety of different linkages that allow the neural network to expand into maturity.
In addition, current research has shown that NTF secreted by neurons can also act on itself autocrine transmission , or it can be transported down to the axon to act on adjacent neurons. At the same time, glial cells can also secrete NTF to neurons through paracrine secretion.
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In the peripheral nerve, the information transmitted by the NTF reverse signaling pathway must be effectively transmitted over long distances, sometimes even over 1 minute. NTF promotes neuronal survival and differentiation during development, but they can also guide the death of neurons.
As a pro-apoptotic receptor, p75NTFR plays a role in the apoptosis of nervous system development and cell damage. During the process of apoptosis, the p75NTFR expression is increased. If neuronal synapses are not properly connected to the appropriate target, they may become apoptotic.
Cell death mediated by p75NTFR may be important in improving proper neuronal distribution during development. Recent studies have shown that NTF plays an extremely important role in synaptic plasticity in the adult brain.
The structure of the visual dominant column in the cortical layer 4 is strongly influenced by exogenous NTF such as BDNF, indicating the developmental regulation of NTF in the synaptic plasticity of the visual system. In addition, the use of blocking antibodies in the visual system has shown that altering endogenous levels of NTF can dramatically alter its effects.
Recent clinical trials have shown limited efficacy in the treatment of neurodegenerative diseases and psychosis directly with NTF. First, delivering enough NTF to target neurons in the body is a major obstacle.
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Because NTF acts as a macromolecular protein, it is difficult to cross the blood-brain barrier. Second, NTF has a variety of neurological effects in the body.