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Neurotrophic Factors
Published in Martin Berry, Ann Logan, CNS Injuries: Cellular Responses and Pharmacological Strategies, 2019
After a nigrostriatal pathway transection in adult rats, axotomized nigrostriatal neurons die over a 2- to 4-week period and only ∼20% of these neurons survive as confirmed by retrograde labeling with fluorescent markers.115 In contrast, we have shown that a 2-week infusion of BDNF in adult rats close to the rostral pole of the nigral complex almost completely prevented the axotomy-induced death of the nigrostriatal neurons in the rostral half of the nigra (Hagg, T., unpublished observations).116 BDNF was less effective in protecting neurons further away from the rostral infusion site, consistent with the poor diffusion characteristics of BDNF. In contrast, the effects of NT-3, which diffuses better, were similar throughout the nigral nucleus. The rescued neurons had an apparently normal size and morphology. Dose-response curves comparing all neurotrophins revealed that NT-4 was more potent than BDNF, which was more potent than NT-3, and as expected by the lack of TrkA receptors, NGF had no effect. Others had reported that injected BDNF was unable to prevent loss of axotomized nigral neurons,94,114 but given the ED50 of BDNF (10 to 30 µg/d), the tissue concentrations achieved with the intermittent injection protocols in those studies were likely insufficient. This indicates that injections of neurotrophic factors, although perhaps more ideal in some clinical settings, are much less effective than continuous infusions. It also suggests that the neurons are dependent for their survival on higher tissue concentrations or continuous presence of the neurotrophic factors. Consistent with this notion, others have successfully employed an alternative mode of delivery by implanting BDNF-producing fibroblasts in adult rats to prevent MPP+-induced loss of substantia nigra neurons.117,118
The balance between cell survival and death in the placenta: Do neurotrophins have a role?
Published in Systems Biology in Reproductive Medicine, 2022
Prachi Pathare-Ingawale, Preeti Chavan-Gautam
Neurotrophins (NTs) are growth factors that regulate the nervous system’s development, maintenance, and function. The neurotrophin family is comprised of four growth factors; brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), NT-3, and NT-4. Each NT binds to the same low-affinity neurotrophin p75NTR receptor, a member of the TNF superfamily but uses different high-affinity Trk receptors, which are members of the tropomyosin-related kinase (Trk) family. BDNF binds to the high-affinity Trk B receptor, whereas NGF binds to the high-affinity Trk A. NT-4 preferentially activates TrkB, and NT-3 uses the Trk C receptor (Reichardt 2006). Binding of NT to the Trk receptor promotes neuronal survival (Yoon et al. 1998), while binding to the p75NTR receptor promotes apoptosis (DeFreitas et al. 2001). NTs are synthesized as precursor forms (i.e.,pro- NT), and their cleavage by intracellular proteases, such are furin (a pro-convertase), generates a carboxyl-terminal mature NT (Kolbeck et al. 1994; Seidah et al. 1996). Mature NTs preferentially activate the respective Trk receptors to induce cell survival, while pro-NTs, which are also biologically active, preferentially activate the p75NTR receptor to induce apoptosis in neuronal cells (Reichardt 2006). The binding of mature NT to Trk receptors promotes cell survival through activation of various signaling molecules like Ras, Rac, PI3k (phosphoinositide 3- kinase), PLC (Phospholipase C), and MAP (mitogen-activated protein) kinase (Harrington et al. 2002).
Understanding intrinsic survival and regenerative pathways through in vivo and in vitro studies: implications for optic nerve regeneration
Published in Expert Review of Ophthalmology, 2021
For axonal regeneration, the intrinsic regenerative pathways must be activated. Neurotrophic factors including the nerve growth factor (NGF) family members bind to the trk receptors and activate the PI3K/Akt/mTOR pathway (Figure 2). NGF eye drops have been used for patients with retinitis pigmentosa [88]. NT-4 also activates the mTOR pathways which contributed to myelination [89], attenuating neuroinflammation [90], and mediating neurogenesis [91]. Our studies of tissue cultures of retinas have shown that NT-4 is the most neuroprotective and regenerative agent [75–79]. Previous studies indicate that citicoline, TUDCA and NT-4 show neuroprotective effect after optic nerve damage in vivo [92–94]. Thus, we combined citicoline, TUDCA, and NT-4 and applied it tropically to rat eyes after optic nerve crush [81]. The triplet group had the most neuroprotective and regenerative effect for damaged RGCs after optic nerve injury [81]. Therefore, the combined topical instillation of neurotrophic factors may be effective for chronic retinal diseases including diabetic retinopathy. We plan to investigate the efficacy of the topical application of a combination of neurotrophic factors in diabetic animal models in the near future.
Is neurotrophin-3 (NT-3): a potential therapeutic target for depression and anxiety?
Published in Expert Opinion on Therapeutic Targets, 2020
A. S. de Miranda, J. L. V. M. de Barros, Antonio Lucio Teixeira
Neurotrophin-3 (NT-3) is a peptide that belongs to a family of secreted proteins known as neurotrophins that also includes brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin (NT)-4/5. Neurotrophins bind to two different classes of cell surface receptors: i) low-affinity pan75 neurotrophin receptor (p75NTR), a member of the tumor necrosis factor α receptor superfamily, and ii) a family of tropomyosin receptor kinases (Trk)-A, Trk-B, and Trk-C. Both Trk receptors and p75NTR are highly expressed in human cortical and hippocampal brain areas [10,11].