Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

s or small

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

s – 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 kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...

s, usually a

receptor tyrosine kinase Receptor tyrosine kinases (RTKs) are the high- affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kin ...

. 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 The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

and

peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain ...

, 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 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 can signal particular cells to survive, differentiate, or grow. Growth facto ...

, (2)

glial cell-line derived neurotrophic factor family 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 proce ...

(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 Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

'' 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.

List of neurotrophic factors

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

, the CNTF family, and GDNF family.

Neurotrophins

Brain-derived neurotrophic factor

Brain-derived neurotrophic factor Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. 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 canon ...

(BDNF) is structurally similar to NGF, NT-3, and NT-4/5, and shares the

TrkB Tropomyosin receptor kinase B (TrkB), also known as tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the ''NTRK2'' gene. TrkB is a recepto ...

receptor with NT-4. The brain-derived neurotrophic factor/TrkB system promotes

thymocyte A Thymocyte is an immune cell present in the thymus, before it undergoes transformation into a T cell. Thymocytes are produced as stem cells in the bone marrow and reach the thymus via the blood. Thymopoiesis describes the process which turns thymo ...

survival, as studied in the

thymus The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or ''T cells'' mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. ...

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 The visual cortex of the brain is the area of the cerebral cortex that processes visual information. It is located in the occipital lobe. Sensory input originating from the eyes travels through the lateral geniculate nucleus in the thalamus and ...

, enhancing neurogenesis, and improving learning and memory. Specifically, BDNF acts within the

hippocampus The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...

. Studies have shown that corticosterone treatment and

adrenalectomy Adrenalectomy (Latin root Ad "near/at" + renal "related to the kidneys" + Greek '' ‑ectomy'' “out-cutting”; sometimes written as ADX for the procedure or resulting state) is the surgical removal of one ( unilateral) or both (bilateral) adr ...

reduces or upregulated hippocampal BDNF expression. Consistent between human and animal studies, BDNF levels are decreased in those with untreated

major depression Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Introdu ...

. However, the correlation between BDNF levels and depression is controversial.

Nerve growth factor

Nerve growth factor (NGF) uses the high-affinity receptor

TrkA Tropomyosin receptor kinase A (TrkA), also known as high affinity nerve growth factor receptor, neurotrophic tyrosine kinase receptor type 1, or TRK1-transforming tyrosine kinase protein is a protein that in humans is encoded by the ''NTRK1'' gen ...

to promote

myelin Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be ...

ation and the differentiation of neurons. Studies have shown dysregulation of NGF causes

hyperalgesia Hyperalgesia ( or ; 'hyper' from Greek ὑπέρ (huper, “over”), '-algesia' from Greek algos, ἄλγος (pain)) is an abnormally increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves and can ...

and pain. NGF production is highly correlated to the extent of

inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...

. 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 Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...

or arthritis, amongst other conditions.

Neurotrophin-3

Whereas neurotrophic factors within the neurotrophin family commonly have a protein tyrosine kinase receptor (Trk),

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 activi ...

(NT-3) has the unique receptor,

TrkC Tropomyosin receptor kinase C (TrkC), also known as NT-3 growth factor receptor, neurotrophic tyrosine kinase receptor type 3, or TrkC tyrosine kinase is a protein that in humans is encoded by the ''NTRK3'' gene. TrkC is the high affinity catalyt ...

. 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

spleen The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .

intestinal epithelium The intestinal epithelium is the single cell layer that form the Lumen (anatomy), luminal surface (lining) of both the Small intestine, small and large intestine (colon) of the Human gastrointestinal tract, gastrointestinal tract. Composed of ...

but its role in the function of each organ is still unknown.

Neurotrophin-4

CNTF family

The CNTF family of neurotrophic factors includes

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 p ...

(CNTF),

leukemia inhibitory factor Leukemia inhibitory factor, or LIF, is an interleukin 6 class cytokine that affects cell growth by inhibiting differentiation. When LIF levels drop, the cells differentiate. Function LIF derives its name from its ability to induce the terminal ...

(LIF),

interleukin-6 Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene. In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smoo ...

(IL-6),

prolactin Prolactin (PRL), also known as lactotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secreted from the pit ...

growth hormone Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in h ...

, leptin,

interferons Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten the ...

(i.e., interferon-α, ), and

oncostatin M Oncostatin M, also known as OSM, is a protein that in humans is encoded by the ''OSM'' gene. OSM is a pleiotropic cytokine that belongs to the interleukin 6 group of cytokines. Of these cytokines it most closely resembles leukemia inhibitory fact ...

Ciliary neurotrophic factor

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 p ...

affects embryonic motor neurons, dorsal root ganglion sensory neurons, and ciliary neuron hippocampal neurons. It is structurally related to

(LIF),

interleukin 6 Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene. In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smooth ...

(IL-6), and

(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 disease Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...

s. It also has unexpected leptin-like characteristics as it causes weight loss.

GDNF family

The

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 proce ...

includes

glial cell line-derived neurotrophic factor Glial cell line-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, particula ...

(GDNF),

artemin Artemin, also known as enovin or neublastin, is a protein that in humans is encoded by the ''ARTN'' gene. Function Artemin is a neurotrophic factor in the glial cell line-derived neurotrophic factor family of ligands which are a group of lig ...

, neurturin, and persephin.

Glial cell line-derived neurotrophic factor

Glial cell line-derived neurotrophic factor (GDNF) was originally detected as survival promoter derived from a glioma cell. Later studies determined GDNF uses a

and a high-affinity ligand-binding co-receptor

GFRα The GDNF family receptor-α (GFRα) proteins are a group of co-receptors which form complexes with GDNF-family ligands (GFLs) to activate RET, the receptor of the GFLs. The GFRα co-receptors include the following: * GFRα1 – preference for ...

. 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.

Artemin

Neurturin

Persephin

Ephrins

The ephrins are a family of neurotrophic factors that signal through eph receptors, a class of

s; the family of ephrins include ephrin A1, A2, A3, A4, A5, B1, B2, and B3.

EGF and TGF families

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 Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other ...

(TGFβ). They signal through

s and

serine/threonine protein kinase A serine/threonine protein kinase () is a kinase enzyme, in particular a protein kinase, that phosphorylates the OH group of the amino-acid residues serine or threonine, which have similar side chains. At least 350 of the 500+ human prote ...

Other neurotrophic factors

Several other biomolecules that have identified as neurotrophic factors include: glia maturation factor, insulin,

insulin-like growth factor 1 Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults. IGF-1 is a protein that in humans ...

(IGF-1),

vascular endothelial growth factor Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...

(VEGF),

fibroblast growth factor Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by macrophages; they are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in their ...

(FGF),

platelet-derived growth factor Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing blood v ...

(PDGF),

pituitary adenylate cyclase-activating peptide Pituitary adenylate cyclase-activating polypeptide also known as PACAP is a protein that in humans is encoded by the ''ADCYAP1'' gene. pituitary adenylate cyclase-activating polypeptide is similar to vasoactive intestinal peptide. One of its effect ...

(PACAP),

interleukin-1 The Interleukin-1 family (IL-1 family) is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults. Discovery Discovery of these cytokines began with studies on t ...

(IL-1),

interleukin-2 Interleukin-2 (IL-2) is an interleukin, a type of cytokine signaling molecule in the immune system. It is a 15.5–16 kDa protein that regulates the activities of white blood cells (leukocytes, often lymphocytes) that are responsible fo ...

(IL-2), interleukin-3 (IL-3), interleukin-5 (IL-5),

interleukin-8 Interleukin 8 (IL-8 or chemokine (C-X-C motif) ligand 8, CXCL8) is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells and endothelial cells. Endothelial cells store IL-8 in their storage ...

(IL-8), macrophage colony-stimulating factor (M-CSF),

granulocyte-macrophage colony-stimulating factor Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts that ...

(GM-CSF), and

neurotactin Fractalkine, also known as chemokine (C-X3-C motif) ligand 1, is a protein that in humans is encoded by the CX3CL1 gene. Function Fractalkine is a large cytokine protein of 373 amino acids, it contains multiple domains and is the only known me ...

References

{{Growth factor receptor modulators Neurochemistry