Neurotrophic factors (NTFs) are a family ofbiomolecules – nearly all of which arepeptides or smallproteins – that support the growth, survival, anddifferentiation of both developing and mature neurons.[1][2][3] Most NTFs exert their trophic effects on neurons by signaling throughtyrosine kinases,[2] usually areceptor tyrosine kinase. In the mature nervous system, they promote neuronal survival, induce synaptic plasticity, and modulate the formation of long-term memories.[2] Neurotrophic factors also promote the initial growth and development of neurons in thecentral nervous system andperipheral nervous system, and they are capable of regrowing damaged neurons in test tubes and animal models.[1][4] Some neurotrophic factors are also released by the target tissue in order toguide 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.[4] Each family has its own distinctcell signaling mechanisms, although the cellular responses elicited often do overlap.[4]
Currently, neurotrophic factors are being intensely studied for use in bioartificial nerve conduits because they are necessaryin 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 asneural drug delivery systems, they are loosely immobilized such that they can be selectively released at specified times and in specified amounts.[medical citation needed]
 |
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: theneurotrophins, the CNTF family, andGDNF family.[2][5][6]
Brain-derived neurotrophic factor (BDNF) is structurally similar toNGF, NT-3, andNT-4/5,[7] and shares theTrkB receptor with NT-4.[8] The brain-derived neurotrophic factor/TrkB system promotesthymocyte survival, as studied in thethymus of mice.[8] Other experiments suggest BDNF is more important and necessary for neuronal survival than other factors.[5] However, this compensatory mechanism is still not known. Specifically, BDNF promotes survival ofdorsal root ganglion neurons.[7] Even when bound to a truncated TrkB, BDNF still shows growth and developmental roles.[7] Without BDNF (homozygous (-/-)), mice do not survive past three weeks.[7]
Including development, BDNF has important regulatory roles in the development of thevisual cortex, enhancing neurogenesis, and improving learning and memory.[7] Specifically, BDNF acts within thehippocampus. Studies have shown thatcorticosterone treatment andadrenalectomy reduces or upregulated hippocampal BDNF expression.[9] Consistent between human and animal studies, BDNF levels are decreased in those with untreatedmajor depression.[9] However, the correlation between BDNF levels and depression is controversial.[9][10]
Nerve growth factor (NGF) uses the high-affinity receptorTrkA[11][8] to promotemyelination[11] and the differentiation of neurons.[12] Studies have shown dysregulation of NGF causeshyperalgesia and pain.[8][12] NGF production is highly correlated to the extent ofinflammation. Even though it is clear that exogenous administration of NGF helps decrease tissue inflammation, the molecular mechanisms are still unknown.[12] Moreover, blood NGF levels are increased in times of stress, duringimmune disease, and withasthma orarthritis, amongst other conditions.[8][12]
Whereas neurotrophic factors within the neurotrophin family commonly have a proteintyrosine kinase receptor (Trk),Neurotrophin-3 (NT-3) has the unique receptor,TrkC.[8] In fact, the discovery of the different receptors helped differentiate scientists' understanding and classification of NT-3.[13] NT-3 does share similar properties with other members of this class, and is known to be important in neuronal survival.[13] The NT-3 protein is found within thethymus,spleen,intestinal epithelium but its role in the function of each organ is still unknown.[8]
![[icon]](/mt/?noimg=&dark=on&url=https%3a%2f%2fen.wikipedia.org%2fwiki%2fFile%3aWiki_letter_w_cropped.svg) | This sectionneeds expansion. You can help byadding to it.(November 2017) |
The CNTF family of neurotrophic factors includesciliary neurotrophic factor (CNTF),leukemia inhibitory factor (LIF),interleukin-6 (IL-6),prolactin,growth hormone,leptin,interferons (i.e., interferon-α,-β, and -γ), andoncostatin M.[2]
Ciliary neurotrophic factor affects embryonicmotor neurons,dorsal root ganglion sensory neurons, and ciliary neuron hippocampal neurons.[14] It is structurally related toleukemia inhibitory factor (LIF),interleukin 6 (IL-6), andoncostatin M (OSM).[15] 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 degenerativemotor neuron diseases.[16] It also has unexpectedleptin-like characteristics as it causes weight loss.[14]
TheGDNF family of ligands includesglial cell line-derived neurotrophic factor (GDNF),artemin,neurturin, andpersephin.[2]
Glial cell line-derived neurotrophic factor (GDNF) was originally detected as survival promoter derived from aglioma cell. Later studies determined GDNF uses areceptor tyrosine kinase and a high-affinity ligand-binding co-receptorGFRα.[17] GDNF has an especially strong affinity fordopaminergic (DA) neurons.[5] 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 reduceaxotomy.[5]
Theephrins are a family of neurotrophic factors that signal througheph receptors, a class ofreceptor tyrosine kinases;[2] the family of ephrins include ephrinA1,A2,A3,A4,A5,B1,B2, andB3.
The EGF and TGF families of neurotrophic factors are composed ofepidermal growth factor, theneuregulins,transforming growth factor alpha (TGFα), andtransforming growth factor beta (TGFβ).[2] They signal throughreceptor tyrosine kinases andserine/threonine protein kinases.[2]
| This sectionneeds expansion. You can help byadding to it.(November 2017) |
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), andneurotactin.[2]
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).