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.[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: the neurotrophins, the CNTF family, and GDNF family.[2][5][6]
Brain-derived neurotrophic factor (BDNF) is structurally similar to NGF, NT-3, and NT-4/5,[7] and shares the TrkB receptor with NT-4.[8] The brain-derived neurotrophic factor/TrkB system promotes thymocyte survival, as studied in the thymus 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 of dorsal 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 the visual cortex, enhancing neurogenesis, and improving learning and memory.[7] Specifically, BDNF acts within the hippocampus. Studies have shown that corticosterone treatment and adrenalectomy reduces or upregulated hippocampal BDNF expression.[9] Consistent between human and animal studies, BDNF levels are decreased in those with untreated major depression.[9] However, the correlation between BDNF levels and depression is controversial.[9][10]
Nerve growth factor
Nerve growth factor (NGF) uses the high-affinity receptor TrkA[11][8] to promote myelination[11] and the differentiation of neurons.[12] Studies have shown dysregulation of NGF causes hyperalgesia and pain.[8][12] 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.[12] Moreover, blood NGF levels are increased in times of stress, during immune disease, and with asthma or arthritis, amongst other conditions.[8][12]
Neurotrophin-3
Whereas neurotrophic factors within the neurotrophin family commonly have a protein tyrosine 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 the thymus, spleen, intestinal epithelium but its role in the function of each organ is still unknown.[8]
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.[17] GDNF has an especially strong affinity for dopaminergic (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 reduce axotomy.[5]
^ ab"Neurotrophic factors". Nature Publishing Group. Retrieved 31 May 2016. 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.
^ abcdefghijMalenka RC, Nestler EJ, Hyman SE (2009). "Chapter 8: Atypical Neurotransmitters". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 199, 211–221. ISBN9780071481274. 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.
^Zigmond MJ, Cameron JL, Hoffer BJ, Smeyne RJ (2012). "Neurorestoration by physical exercise: moving forward". Parkinsonism Relat. Disord. 18 (Suppl 1): S147–50. doi:10.1016/S1353-8020(11)70046-3. PMID22166417. As will be discussed below, exercise stimulates the expression of several neurotrophic factors (NTFs).
^Baloh, Robert H; Enomoto, Hideki; Johnson Jr, Eugene M; Milbrandt, Jeffrey (2000-02-01). "The GDNF family ligands and receptors — implications for neural development". Current Opinion in Neurobiology. 10 (1): 103–110. doi:10.1016/S0959-4388(99)00048-3. PMID10679429. S2CID32315320.
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