Neurotrophic factors

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.[1][2][3] Most NTFs exert their trophic effects on neurons by signaling through tyrosine kinases,[2] 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.[2] 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.[1][4] 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.[4] Each family has its own distinct cell 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 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.

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 neurotrophins, the CNTF family, and GDNF family.[2][5][6]

Brain-derived neurotrophic factor

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]

CNTF family

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.[2]

Ciliary neurotrophic factor

Ciliary neurotrophic factor affects embryonic motor neurons, dorsal root ganglion sensory neurons, and ciliary neuron hippocampal neurons.[14] It is structurally related to leukemia inhibitory factor (LIF), interleukin 6 (IL-6), and oncostatin 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 degenerative motor neuron diseases.[16] It also has unexpected leptin-like characteristics as it causes weight loss.[14]

GDNF family

The GDNF family of ligands includes glial cell line-derived neurotrophic factor (GDNF), artemin, neurturin, and persephin.[2]

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 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]

Artemin
Further information: Artemin

Ephrins

The ephrins are a family of neurotrophic factors that signal through eph receptors, a class of receptor tyrosine kinases;[2] 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 (TGFβ).[2] They signal through receptor tyrosine kinases and serine/threonine protein kinases.[2]

Other neurotrophic factors

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.[2]

References
  1. "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.
  2. Malenka 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. ISBN 9780071481274. 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.
  3. 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. PMID 22166417. As will be discussed below, exercise stimulates the expression of several neurotrophic factors (NTFs).
  4. Deister, C.; Schmidt, C.E. (2006). "Optimizing neurotrophic factor combinations for neurite outgrowth". Journal of Neural Engineering. 3 (2): 172–179. doi:10.1088/1741-2560/3/2/011. PMID 16705273.
  5. Henderson, Christopher E (1996-02-01). "Role of neurotrophic factors in neuronal development". Current Opinion in Neurobiology. 6 (1): 64–70. doi:10.1016/S0959-4388(96)80010-9. PMID 8794045. S2CID 29876053.
  6. Ernsberger, Uwe (2008-07-16). "The role of GDNF family ligand signalling in the differentiation of sympathetic and dorsal root ganglion neurons". Cell and Tissue Research. 333 (3): 353–371. doi:10.1007/s00441-008-0634-4. ISSN 0302-766X. PMC 2516536. PMID 18629541.
  7. Binder, Devin K.; Scharfman, Helen E. (2004-01-01). "Mini Review". Growth Factors. 22 (3): 123–131. doi:10.1080/08977190410001723308. ISSN 0897-7194. PMC 2504526. PMID 15518235.
  8. Vega, José A.; García-Suárez, Olivia; Hannestad, Jonas; Pérez-Pérez, Marta; Germanà, Antonino (2003-07-01). "Neurotrophins and the immune system". Journal of Anatomy. 203 (1): 1–19. doi:10.1046/j.1469-7580.2003.00203.x. ISSN 1469-7580. PMC 1571144. PMID 12892403.
  9. Lee, Bun-Hee; Kim, Yong-Ku (2010). "The Roles of BDNF in the Pathophysiology of Major Depression and in Antidepressant Treatment". Psychiatry Investigation. 7 (4): 231–5. doi:10.4306/pi.2010.7.4.231. PMC 3022308. PMID 21253405.
  10. Groves, J. O. (2007-08-14). "Is it time to reassess the BDNF hypothesis of depression?". Molecular Psychiatry. 12 (12): 1079–1088. doi:10.1038/sj.mp.4002075. ISSN 1359-4184. PMID 17700574.
  11. Villoslada, Pablo; Hauser, Stephen L.; Bartke, Ilse; Unger, Jurgen; Heald, Nathan; Rosenberg, Daniel; Cheung, Steven W.; Mobley, William C.; Fisher, Stefan (2000-05-15). "Human Nerve Growth Factor Protects Common Marmosets against Autoimmune Encephalomyelitis by Switching the Balance of T Helper Cell Type 1 and 2 Cytokines within the Central Nervous System". Journal of Experimental Medicine. 191 (10): 1799–1806. doi:10.1084/jem.191.10.1799. ISSN 0022-1007. PMC 2193155. PMID 10811872.
  12. Prencipe, Giusi; Minnone, Gaetana; Strippoli, Raffaele; Pasquale, Loredana De; Petrini, Stefania; Caiello, Ivan; Manni, Luigi; Benedetti, Fabrizio De; Bracci-Laudiero, Luisa (2014-04-01). "Nerve Growth Factor Downregulates Inflammatory Response in Human Monocytes through TrkA". The Journal of Immunology. 192 (7): 3345–3354. doi:10.4049/jimmunol.1300825. ISSN 0022-1767. PMID 24585880.
  13. Snider, W.D; Wright, D.E (1996). "Neurotrophins Cause a New Sensation". Neuron. 16 (2): 229–232. doi:10.1016/s0896-6273(00)80039-2. PMID 8789936.
  14. Lambert, P. D.; Anderson, K. D.; Sleeman, M. W.; Wong, V.; Tan, J.; Hijarunguru, A.; Corcoran, T. L.; Murray, J. D.; Thabet, K. E. (2001-04-10). "Ciliary neurotrophic factor activates leptin-like pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity". Proceedings of the National Academy of Sciences. 98 (8): 4652–4657. doi:10.1073/pnas.061034298. ISSN 0027-8424. PMC 31889. PMID 11259650.
  15. Piquet-Pellorce, C.; Grey, L.; Mereau, A.; Heath, J. K. (1994-08-01). "Are LIF and related cytokines functionally equivalent?". Experimental Cell Research. 213 (2): 340–347. doi:10.1006/excr.1994.1208. ISSN 0014-4827. PMID 8050491.
  16. Sendtner, M.; Schmalbruch, H.; Stöckli, K. A.; Carroll, P.; Kreutzberg, G. W.; Thoenen, H. (1992-08-06). "Ciliary neurotrophic factor prevents degeneration of motor neurons in mouse mutant progressive motor neuronopathy" (PDF). Nature. 358 (6386): 502–504. doi:10.1038/358502a0. PMID 1641039. S2CID 4369702.
  17. 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. PMID 10679429. S2CID 32315320.

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