Neurotropic factors

Neurotropic factors of dopaminergic neurons may represent a potential neuroprotective therapy for Parkinson s disease. Apart from nerve growth factor (NGF), the family of the neurotrophins subsumes at the present time BDNF, neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5). However, the concept of neurotrophic factors as specific, target-derived molecules, each acting on distinct neuronal types, has to be modified because of their high degree of pleiotropism and a... 

Brain-derived neurotropic factor Basic fibroblast growth factor Bromodeoxyuridine Cornu Ammonis... 

Finally, reversed-phase is some times more useful than ion-exchange in displacement chromatography for the purification of proteins. Figure 12.25 shows the separation of recombinant brain derived neurotropic factor from its variants. This separation was an improvement over one obtained by ion-exchange, which could not remove the E. coli protein impurities. The analysis in panel (a) was performed on a column packed with 5 im particles of bonded silica, at 65°C, using a complex TFA-water-acetonitrile gradient. The displacement separation in panel (b) was performed on a column packed with 10 pm OES silica, with a carrier of 16% ACN and 0.15% TFA, at a flow rate of 0.1 mL/min, with a load of 79 mg of protein [63]. 

Figure 12.25 Displacement chromatogram recombinant brain-derived-neurotropic-factor from its variants labeled 1-5 and from E. coli. protein impurities. Displacer 25mM tetra-hexylammonium chloride, (a) Anal3rtical Chromatogram of Feed, (b) Displacement Chromatogram, (c) Purity Histogram, w/w%. Reproduced with permission from K. M. Sunasara, R.G. Rupp, S. M. Cramer, Biotechnol. Progr. 17 (2001) 897 (Figs. 1,6 and 7.).

Bing Z, Pasha TL, Lai P, et al. Expression of glial cell line-derived neurotropic factor receptor alpha-1 in immature teratomas. Am Clin Pathol. 2008 130 892-896. 

Nagahara, A. B. et al. 2009. Neuroprtective effects of brain-derived neurotropic factor in rodent and primate models of Alzheimer s disease. Nat. Med. 2, 1-8. 

Xu, B Kaira, P.S., Moldawer, L.L., Kaira, S.P., 1998. Increased appetite augments hypothalamic NPY Y1 receptor gene expression effects of anorexigenic ciliary neurotropic factor. Regul. Pept. 75-76, 391-395. 

Figure 5 Retinal photomicrographs of transgenic rats carrying the rhodopsin mutation S334ter (A) S334ter untreated eye and (B) CNTF treated eye by bolus intravitreal injection. The CNTF was injected on P9 and the experiment was terminated on P20. Brackets denote ONL. Abbreviations. CNTF, ciliary neurotropic factor ONL, outer nuclei layer. Source From Ref. 11.

Figure 9 Time course of CNTF output (after explanting) and vitreous CNTF levels after NT-501 intraocular implantation in rabbits. Abbreviation CNTF, ciliary neurotropic factor. Source From Ref. 33.

Neurotropic factors (NTFs) are known to be essential for the survival and functional maintenance of nerve cells [54], Decreased availability of NTFs is thought to cause various nerve disorders including Altzheimer s disease [55], For example, nerve growth factor (NGF) was found as a prototypical neurotrophin factor essential for growth and development of neurons in the central as well as peripheral nervous system [56],... 

The use of TEMPO to effect oxidative demercuration was originally demonstrated by Whitesides [16], and is attractive because it gives a functional handle for further structural elaboration. This technique was invoked by Kang in the syntheses of (-t-)-lactacystin and (-l-)-furanomycin [17]. For example, alkene 10 was subjected to mercurioamidation conditions to afford the cyclized organomercury intermediate 11 (Scheme 4). Treatment with lithium borohydride in the presence of TEMPO forms the unstable organomercury hydride. This fragments to release the primary carbon radical, which is trapped by TEMPO to yield the masked alcohol product 12, an intermediate in the synthesis of the neurotropic factor (-l-)-lactacystin. 

Squinto, S.P., Aldrich, T.H., Lindsay, R.M., Morrissey, D.M., Panayotatos, N., Bianco, S.M., Furth, M.E. and Yancopou-los, G.D. (1990) Identification of functional receptors for ciliary neurotropic factor on neuronal cell lines and primary neurons. Neuron 5 757-766. 

Complanadine (155), a member of the family of lycopodium alkaloids, has more recently been identified as an inducer of neurotropic factor excretion. The synthesis of this almost symmetrical alkaloid, potentially interesting for the treatment of diseases of the central nervous system, was based on two late-stage crossed [2 + 2 + 2] pyridine formation reactions that delivered the central bipyridyl unit. 

Knusel, B., Winslow, J.W., Rosenthal, A., Burton, L.E., Seid, D.R, Nikolics, K., and Hefti, F., 1991, Promotion of central cholinergic and dopaminergic neuron differentiation by brain-derived neurotropic factor but not neurotropin 3, Proc. Natl. Acad. Sci. USA., 88 961-965. 

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