Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and differentiation of both developing and mature neurons. Most NTFs exert their trophic effects on neurons by signaling through tyrosine kinases, usually a receptor tyrosine kinase. In the mature nervous system, they promote neuronal survival, induce synaptic plasticity, and modulate the formation of long-term memories. Neurotrophic factors also promote the initial growth and development of neurons in the central nervous system and peripheral nervous system, and they are capable of regrowing damaged neurons in test tubes and animal models. Some neurotrophic factors are also released by the target tissue in order to guide the growth of developing axons. Most neurotrophic factors belong to one of three families: (1) neurotrophins, (2) glial cell-line derived neurotrophic factor family ligands (GFLs), and (3) neuropoietic cytokines. Each family has its own distinct cell signaling mechanisms, although the cellular responses elicited often do overlap.
Currently, neurotrophic factors are being intensely studied for use in bioartificial nerve conduits because they are necessary in vivo for directing axon growth and regeneration. In studies, neurotrophic factors are normally used in conjunction with other techniques such as biological and physical cues created by the addition of cells and specific topographies. The neurotrophic factors may or may not be immobilized to the scaffold structure, though immobilization is preferred because it allows for the creation of permanent, controllable gradients. In some cases, such as neural drug delivery systems, they are loosely immobilized such that they can be selectively released at specified times and in specified amounts.
Although more information is being discovered about neurotrophic factors, their classification is based on different cellular mechanisms and they are grouped into three main families: the neurotrophins, the CNTF family, and GDNF family.
Brain-derived neurotrophic factor (BDNF) is structurally similar to NGF, NT-3, and NT-4/5, and shares the TrkB receptor with NT-4. The brain-derived neurotrophic factor/TrkB system promotes thymocyte survival, as studied in the thymus of mice. Other experiments suggest BDNF is more important and necessary for neuronal survival than other factors. However, this compensatory mechanism is still not known. Specifically, BDNF promotes survival of dorsal root ganglion neurons. Even when bound to a truncated TrkB, BDNF still shows growth and developmental roles. Without BDNF (homozygous (-/-)), mice do not survive past three weeks.
Including development, BDNF has important regulatory roles in the development of the visual cortex, enhancing neurogenesis, and improving learning and memory. Specifically, BDNF acts within the hippocampus. Studies have shown that corticosterone treatment and adrenalectomy reduces or upregulated hippocampal BDNF expression. Consistent between human and animal studies, BDNF levels are decreased in those with untreated major depression. However, the correlation between BDNF levels and depression is controversial.
Nerve growth factor (NGF) uses the high-affinity receptor TrkA to promote myelination and the differentiation of neurons. Studies have shown dysregulation of NGF causes hyperalgesia and pain. NGF production is highly correlated to the extent of inflammation. Even though it is clear that exogenous administration of NGF helps decrease tissue inflammation, the molecular mechanisms are still unknown. Moreover, blood NGF levels are increased in times of stress, during immune disease, and with asthma or arthritis, amongst other conditions.
Whereas neurotrophic factors within the neurotrophin family commonly have a protein tyrosine kinase receptor (Trk), Neurotrophin-3 (NT-3) has the unique receptor, TrkC. In fact, the discovery of the different receptors helped differentiate scientists understanding and classification of NT-3. NT-3 does share similar properties with other members of this class, and is known to be important in neuronal survival. The NT-3 protein is found within the thymus, spleen, intestinal epithelium but its role in the function of each organ is still unknown.
The CNTF family of neurotrophic factors includes ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), interleukin-6 (IL-6), prolactin, growth hormone, leptin, interferons (i.e., interferon-α, -β, and -γ), and oncostatin M.
Ciliary neurotrophic factor affects embryonic motor neurons, dorsal root ganglion sensory neurons, and ciliary neuron hippocampal neurons. It is structurally related to leukemia inhibitory factor (LIF), interleukin 6 (IL-6), and oncostatin M (OSM). CNTF prevents degeneration of motor neurons in rats and mice which increases survival time and motor function of the mice. These results suggest exogenous CNTF could be used as a therapeutic treatment for human degenerative motor neuron diseases. It also has unexpected leptin-like characteristics as it causes weight loss.
Glial cell line-derived neurotrophic factor (GDNF) was originally detected as survival promoter derived from a glioma cell. Later studies determined GDNF uses a receptor tyrosine kinase and a high-affinity ligand-binding co-receptor GFRα. GDNF has an especially strong affinity for dopaminergic (DA) neurons. Specifically, studies have shown GDNF plays a protective role against MPTP toxins for DA neurons. It has also been detected in motor neurons of embryonic rats and is suggested to aid development and to reduce axotomy.
The EGF and TGF families of neurotrophic factors are composed of epidermal growth factor, the neuregulins, transforming growth factor alpha (TGFα), and transforming growth factor beta (TGFβ). They signal through receptor tyrosine kinases and serine/threonine protein kinases.
Several other biomolecules that have identified as neurotrophic factors include: glia maturation factor, insulin, insulin-like growth factor 1 (IGF-1), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), pituitary adenylate cyclase-activating peptide (PACAP), interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-3 (IL-3), interleukin-5 (IL-5), interleukin-8 (IL-8), macrophage colony-stimulating factor (M-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and neurotactin.
Neurotrophic factors are molecules that enhance the growth and survival potential of neurons. They play important roles in both development, where they can act as guidance cues for developing neurons, and in the mature nervous system, where they are involved in neuronal survival, synaptic plasticity and the formation of long-lasting memories.
Neurotrophic factors are polypeptides or small proteins that support the growth, differentiation, and survival of neurons. They produce their effects by activation of tyrosine kinases.
As will be discussed below, exercise stimulates the expression of several neurotrophic factors (NTFs).
Artemin, also known as enovin or neublastin, is a protein that in humans is encoded by the ARTN gene.Brain-derived neurotrophic factor
Brain-derived neurotrophic factor, also known as BDNF, is a protein that, in humans, is encoded by the BDNF Gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canonical nerve growth factor. Neurotrophic factors are found in the brain and the periphery.Cenegermin
Cenegermin (planned brand names Oxervate, Sentinel), also known as recombinant human nerve growth factor (rhNGF), is a recombinant form of human nerve growth factor (NGF). It was approved in the European Union as an eye drop formulation for the treatment of moderate or severe neurotrophic keratitis in adults on 6 July 2017. As a recombinant form of NGF, cenegermin is a peripherally selective agonist of the TrkA and LNGFR (p75NTR) which must be administered parenterally. In addition to neurotrophic keratitis, cenegermin is also under development for the treatment of dry eyes, retinitis pigmentosa, and glaucoma. It was developed by Anabasis Pharma, Dompé Farmaceutici, and Ospedale San Raffaele.Ciliary neurotrophic factor
Ciliary neurotrophic factor is a protein that in humans is encoded by the CNTF gene.The protein encoded by this gene is a polypeptide hormone and neurotrophic factor whose actions have mainly been studied in the nervous system where it promotes neurotransmitter synthesis and neurite outgrowth in certain neural populations including astrocytes. It is a hypothalamic neuropeptide that is a potent survival factor for neurons and oligodendrocytes and may be relevant in reducing tissue destruction during inflammatory attacks. A mutation in this gene, which results in aberrant splicing, leads to ciliary neurotrophic factor deficiency, but this phenotype is not causally related to neurologic disease. In addition to the predominant monocistronic transcript originating from this locus, the gene is also cotranscribed with the upstream ZFP91 gene. Cotranscription from the two loci results in a transcript that contains a complete coding region for the zinc finger protein but lacks a complete coding region for ciliary neurotrophic factor.CNTF has also been shown to be expressed by cells on the bone surface, and to reduce the activity of bone-forming cells (osteoblasts).Ephrin
Ephrins (also known as ephrin ligands or Eph family receptor interacting proteins) are a family of proteins that serve as the ligands of the eph receptor. Eph receptors in turn compose the largest known subfamily of receptor protein-tyrosine kinases (RTKs).
Since ephrin ligands (ephrins) and Eph receptors (Ephs) are both membrane-bound proteins, binding and activation of Eph/ephrin intracellular signaling pathways can only occur via direct cell-cell interaction. Eph/ephrin signaling regulates a variety of biological processes during embryonic development including the guidance of axon growth cones, formation of tissue boundaries, cell migration, and segmentation. Additionally, Eph/ephrin signaling has recently been identified to play a critical role in the maintenance of several processes during adulthood including long-term potentiation, angiogenesis, and stem cell differentiation.GDNF family of ligands
The GDNF family of ligands (GFL) consists of four neurotrophic factors: glial cell line-derived neurotrophic factor (GDNF), neurturin (NRTN), artemin (ARTN), and persephin (PSPN). GFLs have been shown to play a role in a number of biological processes including cell survival, neurite outgrowth, cell differentiation and cell migration. In particular signalling by GDNF promotes the survival of dopaminergic neurons.Glia maturation factor
Glia maturation factor is a neurotrophic factor implicated in nervous system development, angiogenesis and immune function.
The structures of mouse glia maturation factors beta and gamma, solved by both crystallography and NMR, reveal similarities and critical differences with ADF-H (actin depolymerization factor homology) domains and suggest new means of experimentally addressing the function of this protein family.Glial cell line-derived neurotrophic factor
Glial cell-derived neurotrophic factor (GDNF) is a protein that, in humans, is encoded by the GDNF gene. GDNF is a small protein that potently promotes the survival of many types of neurons. It signals through GFRα receptors, particularly GFRα1.Ladostigil
Ladostigil (TV-3,326) is a novel neuroprotective agent being investigated for the treatment of neurodegenerative disorders like Alzheimer's disease, Lewy body disease, and Parkinson's disease. It acts as a reversible acetylcholinesterase and butyrylcholinesterase inhibitor, and an irreversible monoamine oxidase B inhibitor, and combines the mechanisms of action of older drugs like rivastigmine and rasagiline into a single molecule. In addition to its neuroprotective properties, ladostigil enhances the expression of neurotrophic factors like GDNF and BDNF, and may be capable of reversing some of the damage seen in neurodegenerative diseases via the induction of neurogenesis. Ladostigil also has antidepressant effects, and may be useful for treating comorbid depression and anxiety often seen in such diseases as well.Nerve injury
Nerve injury is injury to nervous tissue. There is no single classification system that can describe all the many variations of nerve injury. In 1941, Seddon introduced a classification of nerve injuries based on three main types of nerve fiber injury and whether there is continuity of the nerve. Usually, however, (peripheral) nerve injury is classified in five stages, based on the extent of damage to both the nerve and the surrounding connective tissue, since supporting glial cells may be involved. Unlike in the central nervous system, neuroregeneration in the peripheral nervous system is possible. The processes that occur in peripheral regeneration can be divided into the following major events: Wallerian degeneration, axon regeneration/growth, and nerve reinnervation. The events that occur in peripheral regeneration occur with respect to the axis of the nerve injury. The proximal stump refers to the end of the injured neuron that is still attached to the neuron cell body; it is the part that regenerates. The distal stump refers to the end of the injured neuron that is still attached to the end of the axon; it is the part of the neuron that will degenerate but that remains in the area toward which the regenerating axon grows. The study of peripheral nerve injury began during the American Civil War and has greatly expanded to the point of using growth-promoting molecules.Neuregulin
Neuregulins or neuroregulins are a family of four structurally related proteins that are part of the EGF family of proteins. These proteins have been shown to have diverse functions in the development of the nervous system and play multiple essential roles in vertebrate embryogenesis including: cardiac development, Schwann cell and oligodendrocyte differentiation, some aspects of neuronal development, as well as the formation of neuromuscular synapses.Included in the family are heregulin; neu differentiation factor; acetylcholine receptor synthesis stimulator; glial growth factor; and sensory and motor-neuron derived factor. Multiple family members are generated by alternate splicing or by use of several cell type-specific transcription initiation sites. In general, they bind to and activate the erbB family of receptor tyrosine kinases (erbB2 (HER2), erbB3 (HER3), and erbB4 (HER4)), functioning both as heterodimers and homodimers.Neuregulin 2
Neuregulin 2, also known as NRG2, is a protein which in humans is encoded by the NRG2 gene.Neuregulin 4
Neuregulin 4 also known as NRG4 is a member of the neuregulin protein family which in humans is encoded by the NRG4 gene.Neurochemical
A neurochemical is a small organic molecule or peptide that participates in neural activity. The science of neurochemistry studies the functions of neurochemicals.Neurotrophin
Neurotrophins are a family of proteins that induce the survival, development, and function of neurons.
They belong to a class of growth factors, secreted proteins that are capable of signaling particular cells to survive, differentiate, or grow. Growth factors such as neurotrophins that promote the survival of neurons are known as neurotrophic factors. Neurotrophic factors are secreted by target tissue and act by preventing the associated neuron from initiating programmed cell death – thus allowing the neurons to survive. Neurotrophins also induce differentiation of progenitor cells, to form neurons.
Although the vast majority of neurons in the mammalian brain are formed prenatally, parts of the adult brain (for example, the hippocampus) retain the ability to grow new neurons from neural stem cells, a process known as neurogenesis. Neurotrophins are chemicals that help to stimulate and control neurogenesis.Neurotrophin-3
Neurotrophin-3 is a protein that in humans is encoded by the NTF3 gene.The protein encoded by this gene, NT-3, is a neurotrophic factor in the NGF (Nerve Growth Factor) family of neurotrophins. It is a protein growth factor which has activity on certain neurons of the peripheral and central nervous system; it helps to support the survival and differentiation of existing neurons, and encourages the growth and differentiation of new neurons and synapses. NT-3 was the third neurotrophic factor to be characterized, after nerve growth factor (NGF) and BDNF (Brain Derived Neurotrophic Factor).Neurotrophin-4
Neurotrophin-4 (NT-4), also known as neurotrophin-5 (NT-5), is a protein that in humans is encoded by the NTF4 gene. It is a neurotrophic factor that signals predominantly through the TrkB receptor tyrosine kinase.Neurturin
Neurturin (NRTN) is a protein. Neurturin belongs to the glial cell-line derived neurotrophic factor (GDNF) family of neurotrophic factors, which regulate the survival and function of neurons. Neurturin’s role as a growth factor places it in the TGF-beta (transforming growth factor) subfamily along with its homologs persephin, artemin, and GDNF. It is also considered a trophic factor and critical in the development and growth of neurons in the brain. Neurotrophic factors like neurturin have been tested in several clinical trial setting for the potential treatment of neurodegenerative diseases, specifically Parkinsons Disease.Persephin
Persephin is a neurotrophic factor in the glial cell line-derived neurotrophic factor (GDNF) family.