Journal articles on the topic 'Neurite regeneration'
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1
Walker, Sarah, Gaynor Spencer, Aleksandar Necakov, and Robert Carlone. "Identification and Characterization of microRNAs during Retinoic Acid-Induced Regeneration of a Molluscan Central Nervous System." International Journal of Molecular Sciences 19, no. 9 (September 13, 2018): 2741. http://dx.doi.org/10.3390/ijms19092741.
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Retinoic acid (RA) is the biologically active metabolite of vitamin A and has become a well-established factor that induces neurite outgrowth and regeneration in both vertebrates and invertebrates. However, the underlying regulatory mechanisms that may mediate RA-induced neurite sprouting remain unclear. In the past decade, microRNAs have emerged as important regulators of nervous system development and regeneration, and have been shown to contribute to processes such as neurite sprouting. However, few studies have demonstrated the role of miRNAs in RA-induced neurite sprouting. By miRNA sequencing analysis, we identify 482 miRNAs in the regenerating central nervous system (CNS) of the mollusc Lymnaea stagnalis, 219 of which represent potentially novel miRNAs. Of the remaining conserved miRNAs, 38 show a statistically significant up- or downregulation in regenerating CNS as a result of RA treatment. We further characterized the expression of one neuronally-enriched miRNA upregulated by RA, miR-124. We demonstrate, for the first time, that miR-124 is expressed within the cell bodies and neurites of regenerating motorneurons. Moreover, we identify miR-124 expression within the growth cones of cultured ciliary motorneurons (pedal A), whereas expression in the growth cones of another class of respiratory motorneurons (right parietal A) was absent in vitro. These findings support our hypothesis that miRNAs are important regulators of retinoic acid-induced neuronal outgrowth and regeneration in regeneration-competent species.
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Alhajlah, Sharif, Adam M. Thompson, and Zubair Ahmed. "Overexpression of Reticulon 3 Enhances CNS Axon Regeneration and Functional Recovery after Traumatic Injury." Cells 10, no. 8 (August 6, 2021): 2015. http://dx.doi.org/10.3390/cells10082015.
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CNS neurons are generally incapable of regenerating their axons after injury due to several intrinsic and extrinsic factors, including the presence of axon growth inhibitory molecules. One such potent inhibitor of CNS axon regeneration is Reticulon (RTN) 4 or Nogo-A. Here, we focused on RTN3 as its contribution to CNS axon regeneration is currently unknown. We found that RTN3 expression correlated with an axon regenerative phenotype in dorsal root ganglion neurons (DRGN) after injury to the dorsal columns, a well-characterised model of spinal cord injury. Overexpression of RTN3 promoted disinhibited DRGN neurite outgrowth in vitro and dorsal column axon regeneration/sprouting and electrophysiological, sensory and locomotor functional recovery after injury in vivo. Knockdown of protrudin, however, ablated RTN3-enhanced neurite outgrowth/axon regeneration in vitro and in vivo. Moreover, overexpression of RTN3 in a second model of CNS injury, the optic nerve crush injury model, enhanced retinal ganglion cell (RGC) survival, disinhibited neurite outgrowth in vitro and survival and axon regeneration in vivo, an effect that was also dependent on protrudin. These results demonstrate that RTN3 enhances neurite outgrowth/axon regeneration in a protrudin-dependent manner after both spinal cord and optic nerve injury.
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Yilmaz-Bayraktar, Suheda, Jana Schwieger, Verena Scheper, Thomas Lenarz, Ulrike Böer, Michaela Kreienmeyer, Mariela Torrente, and Theodor Doll. "Decellularized equine carotid artery layers as matrix for regenerated neurites of spiral ganglion neurons." International Journal of Artificial Organs 43, no. 5 (August 22, 2019): 332–42. http://dx.doi.org/10.1177/0391398819868481.
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Today’s best solution in compensating for sensorineural hearing loss is the cochlear implant, which electrically stimulates the spiral ganglion neurons in the inner ear. An optimum hearing impression is not ensured due to, among other reasons, a remaining anatomical gap between the spiral ganglion neurons and the implant electrodes. The gap could be bridged via pharmacologically triggered neurite growth toward the electrodes if biomaterials for neurite guidance could be provided. For this, we investigated the suitability of decellularized tissue. We compared three different layers (tunica adventitia, tunica media, and tunica intima) of decellularized equine carotid arteries in a preliminary approach. Rat spiral ganglia explants were cultured on decellularized equine carotid artery layers and neurite sprouting was assessed quantitatively. Generally, neurite outgrowth was possible and it was most prominent on the intima (in average 83 neurites per spiral ganglia explants, followed by the adventitia (62 neurites) and the lowest growth on the media (20 neurites). Thus, decellularized equine carotid arteries showed promising effects on neurite regeneration and can be developed further as efficient biomaterials for neural implants in hearing research.
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Lu, Wen, Margot Lakonishok, and Vladimir I. Gelfand. "Kinesin-1–powered microtubule sliding initiates axonal regeneration in Drosophila cultured neurons." Molecular Biology of the Cell 26, no. 7 (April 2015): 1296–307. http://dx.doi.org/10.1091/mbc.e14-10-1423.
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Understanding the mechanism underlying axon regeneration is of great practical importance for developing therapeutic treatment for traumatic brain and spinal cord injuries. Dramatic cytoskeleton reorganization occurs at the injury site, and microtubules have been implicated in the regeneration process. Previously we demonstrated that microtubule sliding by conventional kinesin (kinesin-1) is required for initiation of neurite outgrowth in Drosophila embryonic neurons and that sliding is developmentally down-regulated when neurite outgrowth is completed. Here we report that mechanical axotomy of Drosophila neurons in culture triggers axonal regeneration and regrowth. Regenerating neurons contain actively sliding microtubules; this sliding, like sliding during initial neurite outgrowth, is driven by kinesin-1 and is required for axonal regeneration. The injury induces a fast spike of calcium, depolymerization of microtubules near the injury site, and subsequent formation of local new microtubule arrays with mixed polarity. These events are required for reactivation of microtubule sliding at the initial stages of regeneration. Furthermore, the c-Jun N-terminal kinase pathway promotes regeneration by enhancing microtubule sliding in injured mature neurons.
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Ahmed, Morgan-Warren, Berry, Scott, and Logan. "Effects of siRNA-Mediated Knockdown of GSK3β on Retinal Ganglion Cell Survival and Neurite/Axon Growth." Cells 8, no. 9 (August 22, 2019): 956. http://dx.doi.org/10.3390/cells8090956.
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There are contradictory reports on the role of the serine/threonine kinase isoform glycogen synthase kinase-3β (GSK3β) after injury to the central nervous system (CNS). Some report that GSK3 activity promotes axonal growth or myelin disinhibition, whilst others report that GSK3 activity prevents axon regeneration. In this study, we sought to clarify if suppression of GSK3β alone and in combination with the cellular-stress-induced factor RTP801 (also known as REDD1: regulated in development and DNA damage response protein), using translationally relevant siRNAs, promotes retinal ganglion cell (RGC) survival and neurite outgrowth/axon regeneration. Adult mixed retinal cell cultures, prepared from rats at five days after optic nerve crush (ONC) to activate retinal glia, were treated with siRNA to GSK3β (siGSK3β) alone or in combination with siRTP801 and RGC survival and neurite outgrowth were quantified in the presence and absence of Rapamycin or inhibitory Nogo-A peptides. In in vivo experiments, either siGSK3β alone or in combination with siRTP801 were intravitreally injected every eight days after ONC and RGC survival and axon regeneration was assessed at 24 days. Optimal doses of siGSK3β alone promoted significant RGC survival, increasing the number of RGC with neurites without affecting neurite length, an effect that was sensitive to Rapamycin. In addition, knockdown of GSK3β overcame Nogo-A-mediated neurite growth inhibition. Knockdown of GSK3β after ONC in vivo enhanced RGC survival but not axon number or length, without potentiating glial activation. Knockdown of RTP801 increased both RGC survival and axon regeneration, whilst the combined knockdown of GSK3β and RTP801 significantly increased RGC survival, neurite outgrowth, and axon regeneration over and above that observed for siGSK3β or siRTP801 alone. These results suggest that GSK3β suppression promotes RGC survival and axon initiation whilst, when in combination with RTP801, it also enhanced disinhibited axon elongation.
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Sakane, Ayuko, Kazufumi Honda, and Takuya Sasaki. "Rab13 Regulates Neurite Outgrowth in PC12 Cells through Its Effector Protein, JRAB/MICAL-L2." Molecular and Cellular Biology 30, no. 4 (December 14, 2009): 1077–87. http://dx.doi.org/10.1128/mcb.01067-09.
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ABSTRACT Neurite outgrowth is the first step in the processes of neuronal differentiation and regeneration and leads to synaptic polarization and plasticity. Rab13 small G protein shows an increased mRNA expression level during neuronal regeneration; it is therefore thought to be involved in this process. We previously identified JRAB (junctional Rab13-binding protein)/MICAL-L2 (molecules interacting with CasL-like 2) as a novel Rab13 effector protein. Here, we show that Rab13 regulates neurite outgrowth in the rat pheochromocytoma cell line PC12 through an interaction with JRAB/MICAL-L2. The expression of JRAB/MICAL-L2 alone inhibits neurite outgrowth, whereas coexpression of the dominant active form of Rab13 rescues this effect. We also demonstrate an intramolecular interaction between the N-terminal calponin-homology (CH) and LIM domains of JRAB/MICAL-L2 and the C-terminal coiled-coil domain. Finally, we show that the binding of Rab13 to JRAB/MICAL-L2 stimulates the interaction of JRAB/MICAL-L2 with actinin-4, an actin-binding protein, which localizes to the cell body and the tips of the neurites in PC12 cells. These results suggest that Rab13 and JRAB/MICAL-L2 may act to transfer actinin-4 from the cell body to the tips of neurites, where actinin-4 is involved in the reorganization of the actin cytoskeleton which results in neurite outgrowth.
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Santos, Daniel, Francisco Gonzalez-Perez, Xavier Navarro, and Jaume del Valle. "Dose-Dependent Differential Effect of Neurotrophic Factors on In Vitro and In Vivo Regeneration of Motor and Sensory Neurons." Neural Plasticity 2016 (2016): 1–13. http://dx.doi.org/10.1155/2016/4969523.
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Although peripheral axons can regenerate after nerve transection and repair, functional recovery is usually poor due to inaccurate reinnervation. Neurotrophic factors promote directional guidance to regenerating axons and their selective application may help to improve functional recovery. Hence, we have characterized in organotypic cultures of spinal cord and dorsal root ganglia the effect of GDNF, FGF-2, NGF, NT-3, and BDNF at different concentrations on motor and sensory neurite outgrowth. In vitro results show that GDNF and FGF-2 enhanced both motor and sensory neurite outgrowth, NGF and NT-3 were the most selective to enhance sensory neurite outgrowth, and high doses of BDNF selectively enhanced motor neurite outgrowth. Then, NGF, NT-3, and BDNF (as the most selective factors) were delivered in a collagen matrix within a silicone tube to repair the severed sciatic nerve of rats. Quantification of Fluorogold retrolabeled neurons showed that NGF and NT-3 did not show preferential effect on sensory regeneration whereas BDNF preferentially promoted motor axons regeneration. Therefore, the selective effects of NGF and NT-3 shown in vitro are lost when they are applied in vivo, but a high dose of BDNF is able to selectively enhance motor neuron regeneration both in vitro and in vivo.
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Burstein, D. E., P. J. Seeley, and L. A. Greene. "Lithium ion inhibits nerve growth factor-induced neurite outgrowth and phosphorylation of nerve growth factor-modulated microtubule-associated proteins." Journal of Cell Biology 101, no. 3 (September 1, 1985): 862–70. http://dx.doi.org/10.1083/jcb.101.3.862.
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LiCl (2.5-20 mM) reversibly suppressed nerve growth factor (NGF)-induced neurite outgrowth by cultured rat PC 12 pheochromocytoma cells. Similar concentrations of LiCl also reversibly blocked NGF-dependent regeneration of neurites by PC12 cells that had been primed by long-term pre-exposure to NGF and by cultured newborn mouse sympathetic neurons. In contrast, transcription-dependent responses of PC12 cells to NGF such as priming and induction of the NGF-inducible large external glycoprotein, occurred despite the presence of Li+. SDS PAGE analysis of total cellular phosphoproteins (labeled by 2-h exposure to 32P-orthophosphate) from neurite-bearing primed PC12 cells revealed that Li+ reversibly inhibited the phosphorylation of a band of Mr 64,000 that was barely detectable in NGF-untreated PC12 cells. However, Li+ did not appear to affect the labeling of other phosphoproteins in either NGF-primed or untreated PC12 cultures, nor did it affect the rapid increase in phosphorylation of several proteins that occurs when NGF is first added to unprimed cultures. Several criteria indicated that the NGF-inducible phosphoprotein of Mr 64,000 is a microtubule-associated protein (MAP). Of the NGF-inducible phosphorylated MAPs that have been detected in PC12 cells (Mr 64,000, 72,000, 80,000, and 320,000), several (Mr 64,000, 72,000, and 80,000) were found to be substantially less phosphorylated in the presence of Li+. Neither a phorbol ester tumor promotor nor permeant cAMP analogs reversed the inhibitory effects of Li+ on neurite outgrowth or on phosphorylation of the component of Mr 64,000. Microtubules are a major and required constituent of neurites, and MAPs may regulate the assembly and stability of neuritic microtubules. The observation that Li+ selectively inhibits NGF-induced neurite outgrowth and MAP phosphorylation suggests a possible causal relationship between these two events.
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Nishiyama, N., K. Abe, H. Katsuki, and H. Saito. "Pharmacological analysis of neurite regeneration." Pathophysiology 1 (November 1994): 77. http://dx.doi.org/10.1016/0928-4680(94)90178-3.
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Gey, Manuel, Renate Wanner, Corinna Schilling, Maria T. Pedro, Daniela Sinske, and Bernd Knöll. "Atf3 mutant mice show reduced axon regeneration and impaired regeneration-associated gene induction after peripheral nerve injury." Open Biology 6, no. 8 (August 2016): 160091. http://dx.doi.org/10.1098/rsob.160091.
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Axon injury in the peripheral nervous system (PNS) induces a regeneration-associated gene (RAG) response. Atf3 (activating transcription factor 3) is such a RAG and ATF3's transcriptional activity might induce ‘effector’ RAGs (e.g. small proline rich protein 1a ( Sprr1a ) , Galanin ( Gal ) , growth-associated protein 43 ( Gap43 )) facilitating peripheral axon regeneration. We provide a first analysis of Atf3 mouse mutants in peripheral nerve regeneration. In Atf3 mutant mice, facial nerve regeneration and neurite outgrowth of adult ATF3-deficient primary dorsal root ganglia neurons was decreased. Using genome-wide transcriptomics, we identified a neuropeptide-encoding RAG cluster (vasoactive intestinal peptide ( Vip ) , Ngf, Grp, Gal, Pacap ) regulated by ATF3. Exogenous administration of neuropeptides enhanced neurite growth of Atf3 mutant mice suggesting that these molecules might be effector RAGs of ATF3's pro-regenerative function. In addition to the induction of growth-promoting molecules, we present data that ATF3 suppresses growth-inhibiting molecules such as chemokine (C-C motif) ligand 2. In summary, we show a pro-regenerative ATF3 function during PNS nerve regeneration involving transcriptional activation of a neuropeptide-encoding RAG cluster. ATF3 is a general injury-inducible factor, therefore ATF3-mediated mechanisms identified herein might apply to other cell and injury types.
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Wiatrak, Benita, Paulina Sobierajska, Marta Szandruk-Bender, Paulina Jawien, Maciej Janeczek, Maciej Dobrzynski, Patrycja Pistor, Adam Szelag, and Rafal J. Wiglusz. "Nanohydroxyapatite as a Biomaterial for Peripheral Nerve Regeneration after Mechanical Damage—In Vitro Study." International Journal of Molecular Sciences 22, no. 9 (April 24, 2021): 4454. http://dx.doi.org/10.3390/ijms22094454.
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Hydroxyapatite has been used in medicine for many years as a biomaterial or a cover for other biomaterials in orthopedics and dentistry. This study characterized the physicochemical properties (structure, particle size and morphology, surface properties) of Li+- and Li+/Eu3+-doped nanohydroxyapatite obtained using the wet chemistry method. The potential regenerative properties against neurite damage in cultures of neuron-like cells (SH-SY5Y and PC12 after differentiation) were also studied. The effect of nanohydroxyapatite (nHAp) on the induction of repair processes in cell cultures was assessed in tests of metabolic activity, the level of free oxygen radicals and nitric oxide, and the average length of neurites. The study showed that nanohydroxyapatite influences the increase in mitochondrial activity, which is correlated with the increase in the length of neurites. It has been shown that the doping of nanohydroxyapatite with Eu3+ ions enhances the antioxidant properties of the tested nanohydroxyapatite. These basic studies indicate its potential application in the treatment of neurite damage. These studies should be continued in primary neuronal cultures and then with in vivo models.
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Liu, Yonghua, Ying Chen, Xiang Lu, Youhua Wang, Yinong Duan, Chun Cheng, and Aiguo Shen. "SCYL1BP1 modulates neurite outgrowth and regeneration by regulating the Mdm2/p53 pathway." Molecular Biology of the Cell 23, no. 23 (December 2012): 4506–14. http://dx.doi.org/10.1091/mbc.e12-05-0362.
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SCY1-like 1–binding protein 1 (SCYL1BP1) is a newly identified transcriptional activator domain containing a protein with many unknown biological functions. Recently emerging evidence has revealed that it is a novel regulator of the p53 pathway, which is required for neurite outgrowth and regeneration. Here we present evidence that SCYL1BP1 inhibits nerve growth factor–mediated neurite outgrowth in PC12 cells and affects morphogenesis of primary cortical neurons by strongly decreasing the p53 protein level in vitro, all of which depends on SCYL1BP1's transcriptional activator domain. Exogenous p53 rescues neurite outgrowth and neuronal morphogenesis defects caused by SCYL1BP1. Furthermore, SCYL1BP1 can directly induce Mdm2 transcription, whereas inhibiting the function of Mdm2 by specific small interfering RNAs results in partial rescue of neurite outgrowth and neuronal morphogenesis defects induced by SCYL1BP1. In vivo experiments show that SCYL1BP1 can also depress axonal regeneration, whereas inhibiting the function of SCYL1BP1 by specific short hairpin RNA enhances it. Taken together, these data strongly suggested that SCYL1BP1 is a novel transcriptional activator in neurite outgrowth by directly modulating the Mdm2/p53-dependent pathway, which might play an important role in CNS development and axonal regeneration after injury.
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Seilheimer, B., and M. Schachner. "Studies of adhesion molecules mediating interactions between cells of peripheral nervous system indicate a major role for L1 in mediating sensory neuron growth on Schwann cells in culture." Journal of Cell Biology 107, no. 1 (July 1, 1988): 341–51. http://dx.doi.org/10.1083/jcb.107.1.341.
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The involvement of the adhesion molecules L1, N-CAM, and J1 in adhesion and neurite outgrowth in the peripheral nervous system was investigated. We prepared Schwann cells and fibroblasts (from sciatic nerves) and neurons (from dorsal root ganglia) from 1-d mice. These cells were allowed to interact with each other in a short-term adhesion assay. We also measured outgrowth of dorsal root ganglion neurons on Schwann cell and fibroblast monolayers. Schwann cells (which express L1, N-CAM, and J1) adhered most strongly to dorsal root ganglion neurons by an L1-dependent mechanism and less by N-CAM and J1. Schwann cell-Schwann cell adhesion was mediated by L1 and N-CAM, but not J1. Adhesion of fibroblasts (which express N-CAM, but not L1 or J1) to neurons or Schwann cells was mediated by L1 and N-CAM and not J1. However, inhibition by L1 and N-CAM antibodies was found to be less pronounced with fibroblasts than with Schwann cells. N-CAM was also strongly involved in fibroblast-fibroblast adhesion. Neurite outgrowth was most extensive on Schwann cells and less on fibroblasts. A difference in extent of neurite elongation was seen between small- (10-20 microns) and large- (20-35 microns) diameter neurons, with the larger neurons tending to exhibit longer neurites. Fab fragments of polyclonal L1, N-CAM, and J1 antibodies exerted slightly different inhibitory effects on neurite outgrowth, depending on whether the neurites were derived from small or large neurons. L1 antibodies interfered most strikingly with neurite outgrowth on Schwann cells (inhibition of 88% for small and 76% for large neurons), while no inhibition was detectable on fibroblasts. Similarly, although to a smaller extent than L1, N-CAM appeared to be involved in neurite outgrowth on Schwann cells and not on fibroblasts. Antibodies to J1 only showed a very small effect on neurite outgrowth of large neurons on Schwann cells. These observations show for the first time that identified adhesion molecules are potent mediators of glia-dependent neurite formation and attribute to L1 a predominant role in neurite outgrowth on Schwann cells which may be instrumental in regeneration.
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Bikbova, Guzel, Toshiyuki Oshitari, Takayuki Baba, and Shuichi Yamamoto. "Altered Expression of NF-κB and SP1 after Exposure to Advanced Glycation End-Products and Effects of Neurotrophic Factors in AGEs Exposed Rat Retinas." Journal of Diabetes Research 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/543818.
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To determine the effect of advanced glycation end-products (AGEs) on neurite regeneration, and also to determine the regenerative effects of different neurotrophic factors (NTFs) on rat retinal explants, the retinas of SD rats were cultured in three-dimensional collagen gels and incubated in 6 types of media: (1) serum-free control culture media; (2) 100 μg/mL AGEs-BSA media; (3) AGEs-BSA + 100 ng/mL neurotrophin-4 (NT-4) media; (4) AGEs-BSA + 100 ng/mL hepatocyte growth factor media; (5) AGEs-BSA + 100 ng/mL glial cell line-derived neurotrophic factor media; or (6) AGEs-BSA + 100 µM tauroursodeoxycholic acid media. After 7 days, the number of regenerating neurites was counted. The explants were immunostained for nuclear factor-κB (NF-κB) and specificity protein 1 (SP1). Statistical analyses were performed by one-way ANOVA. In retinas incubated with AGEs, the numbers of neurites were fewer than in control. All of the NTFs increased the number of neurites, and the increase was more significant in the NT-4 group. The number of NF-κB and SP1 immunopositive cells was higher in retinas exposed to AGEs than in control. All of the NTFs decreased the number of NF-κB immunopositive cells but did not significantly affect SP1 expression. These results demonstrate the potential of the NTFs as axoprotectants in AGEs exposed retinal neurons.
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Han, Sungmin, Jinyoung Park, Won Seok Choi, and Inchan Youn. "Ultrasound Stimulation Increases Neurite Regeneration in Injured Dorsal Root Ganglion Neurons through Mammalian Target of Rapamycin Activation." Brain Sciences 10, no. 7 (June 30, 2020): 409. http://dx.doi.org/10.3390/brainsci10070409.
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Ultrasound stimulation (US) is reported to be a safe and useful technology for improving injured nerve regeneration. However, the intracellular mechanisms underlying its stimulatory effects are only partially understood. Mammalian target of rapamycin (mTOR) signaling is involved in neuronal survival and axonal outgrowth. In this study, we investigated the effect of US on regeneration of injured dorsal root ganglion (DRG) neurons and activation of the mTOR pathway. We showed that US significantly increased neurite regeneration and enhanced mTOR activation. Moreover, the expression of growth-associated protein-43 (GAP-43), a crucial factor for axonal outgrowth and regeneration in neurons, was significantly increased by US. These data suggest that US-induced neurite regeneration is mediated by upregulation of mTOR activity, which promotes the regeneration of injured DRG neurons.
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Aigner, L., and P. Caroni. "Depletion of 43-kD growth-associated protein in primary sensory neurons leads to diminished formation and spreading of growth cones." Journal of Cell Biology 123, no. 2 (October 15, 1993): 417–29. http://dx.doi.org/10.1083/jcb.123.2.417.
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The 43-kD growth-associated protein (GAP-43) is a major protein kinase C (PKC) substrate of growing axons, and of developing nerve terminals and glial cells. It is a highly hydrophilic protein associated with the cortical cytoskeleton and membranes. In neurons it is rapidly transported from the cell body to growth cones and nerve terminals, where it accumulates. To define the role of GAP-43 in neurite outgrowth, we analyzed neurite regeneration in cultured dorsal root ganglia (DRG) neurons that had been depleted of GAP-43 with any of three nonoverlapping antisense oligonucleotides. The GAP-43 depletion procedure was specific for this protein and an antisense oligonucleotide to the related PKC substrate MARCKS did not detectably affect GAP-43 immunoreactivity. We report that neurite outgrowth and morphology depended on the levels of GAP-43 in the neurons in a substrate-specific manner. When grown on a laminin substratum, GAP-43-depleted neurons extended longer, thinner and less branched neurites with strikingly smaller growth cones than their GAP-43-expressing counterparts. In contrast, suppression of GAP-43 expression prevented growth cone and neurite formation when DRG neurons were plated on poly-L-ornithine. These findings indicate that GAP-43 plays an important role in growth cone formation and neurite outgrowth. It may be involved in the potentiation of growth cone responses to external signals affecting process formation and guidance.
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Wang, Hua, Cai Zhang, Long-en Yang, and Zhiyou Yang. "Hederagenin Modulates M1 Microglial Inflammatory Responses and Neurite Outgrowth." Natural Product Communications 15, no. 8 (August 2020): 1934578X2094625. http://dx.doi.org/10.1177/1934578x20946252.
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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Neurite atrophy and synaptic loss initiate the onset of neuronal death, while the activated M1 microglia-induced neuroinflammatory microenvironment inhibits neurite regeneration and exacerbates neuronal loss. Thus, optimizing the brain microenvironment using small compounds through suppressing activated M1 microglia and promoting neurite regrowth might be an effective therapeutic strategy for AD. We found that hederagenin (HED), a naturally occurring triterpene compound, inhibited lipopolysaccharide-induced nitric oxide generation and downregulated expression of proinflammatory cytokines, such as tumor necrosis factor-α, interleukin-1β (IL-1β), and IL-6. Further investigation of primary microglia confirmed that HED inhibited Iba-1 positive M1 microglia. However, no changes were seen in CD206 positive M2 microglia polarization. HED remarkably suppressed phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells subunit p65 signaling. In addition, HED ameliorated Aβ25-35-induced neuritic atrophy and neuronal death. Therefore, HED might be a therapeutic candidate for AD.
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Rosso, Gonzalo, Peter Young, and Victor Shahin. "Mechanosensitivity of Embryonic Neurites Promotes Their Directional Extension and Schwann Cells Progenitors Migration." Cellular Physiology and Biochemistry 44, no. 4 (2017): 1263–70. http://dx.doi.org/10.1159/000485485.
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Background/Aims: Migration of Schwann cells (SCs) progenitors and neurite outgrowth from embryonic dorsal root ganglions (DRGs) are two central events during the development of the peripheral nervous system (PNS). How these two enthralling events preceding myelination are promoted is of great relevance from basic research and clinical aspects alike. Recent evidence demonstrates that biophysical cues (extracellular matrix stiffness) and biochemical signaling act in concert to regulate PNS myelination. Microenvironment stiffness of SCs progenitors and embryonic neurites dynamically changes during development. Methods: DRG explants were isolated from day 12.5 to 13.5 mice embryos and plated on laminin-coated substrates with varied stiffness values. After 4 days in culture and immunostaining with specific markers, neurite outgrowth pattern, SCs progenitors migration, and growth cone shape and advance were analyzed with confocal fluorescence microscopy. Results: We found out that growing substrate stiffness promotes directional neurite outgrowth, SCs progenitors migration, growth cone advance and presumably axons fasciculation. Conclusions: DRG explants are in vitro models for the research of PNS development, myelination and regeneration. Consequently, we conclude the following: Our observations point out the importance of mechanosensitivity for the PNS. At the same time, they prompt the investigation of the important yet unclear links between PNS biomechanics and inherited neuropathies with myelination disorders such as Charcot-Marie-Tooth 1A and hereditary neuropathy with liability to pressure palsies. Finally, they encourage the consideration of mechanosensitivity in bioengineering of scaffolds to aid nerve regeneration after injury.
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Marler, Katharine J. M., Robert Kozma, Sohail Ahmed, Jing-Ming Dong, Christine Hall, and Louis Lim. "Outgrowth of Neurites from NIE-115 Neuroblastoma Cells Is Prevented on Repulsive Substrates through the Action of PAK." Molecular and Cellular Biology 25, no. 12 (June 15, 2005): 5226–41. http://dx.doi.org/10.1128/mcb.25.12.5226-5241.2005.
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ABSTRACT In the central nervous system (CNS), damaged axons are inhibited from regeneration by glial scars, where secreted chondroitin sulfate proteoglycan (CSPG) and tenascin repulse outgrowth of neurites, the forerunners of axons and dendrites. During differentiation, these molecules are thought to form boundaries for guiding neurons to their correct targets. In neuroblastoma NIE-115 cells, outgrowth of neurites on laminin could be induced by serum starvation or inhibition of RhoA by Clostridium botulinum C3 toxin. The outgrowing neurites avoided crossing onto the repulsive substrate CSPG or tenascin. This avoidance response was partially overcome on expression of membrane-targeted and kinase-inactive forms of PAK. In these cells, the endogenous PAK isoforms colocalized with actin in distinctive sites, αPAK in the cell center as small clusters and along the neurite shaft and βPAK and γPAK in areas with membrane ruffles and filopodia, respectively. When isoform-specific N-terminal PAK sequences were introduced to interfere with PAK function, substantially more neurites crossed onto CSPG when cells contained a γPAK-derived peptide but not the corresponding αPAK- or βPAK-derived peptide. Thus, while neurite outgrowth can be promoted by RhoA inhibition, overcoming the accompanying repulsive guidance response will require modulation of PAK activity. These results have therapeutic implications for CNS repair processes.
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Lalli, Giovanna, and Alan Hall. "Ral GTPases regulate neurite branching through GAP-43 and the exocyst complex." Journal of Cell Biology 171, no. 5 (December 5, 2005): 857–69. http://dx.doi.org/10.1083/jcb.200507061.
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Neurite branching is essential for the establishment of appropriate neuronal connections during development and regeneration. We identify the small GTPase Ral as a mediator of neurite branching. Active Ral promotes neurite branching in cortical and sympathetic neurons, whereas Ral inhibition decreases laminin-induced branching. In addition, depletion of endogenous Ral by RNA interference decreases branching in cortical neurons. The two Ral isoforms, RalA and -B, promote branching through distinct pathways, involving the exocyst complex and phospholipase D, respectively. Finally, Ral-dependent branching is mediated by protein kinase C–dependent phosphorylation of 43-kD growth-associated protein, a crucial molecule involved in pathfinding, plasticity, and regeneration. These findings highlight an important role for Ral in the regulation of neuronal morphology.
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Granholm, Ann-Charlotte, and Ingrid Strömberg. "Introduction: Factors influencing neurite outgrowth and regeneration." Microscopy Research and Technique 54, no. 5 (August 14, 2001): 271–72. http://dx.doi.org/10.1002/jemt.1139.
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Horn, Eric M., Michael Beaumont, Xiao Zheng Shu, Adrian Harvey, Glenn D. Prestwich, Kris M. Horn, Alan R. Gibson, Mark C. Preul, and Alyssa Panitch. "Influence of cross-linked hyaluronic acid hydrogels on neurite outgrowth and recovery from spinal cord injury." Journal of Neurosurgery: Spine 6, no. 2 (February 2007): 133–40. http://dx.doi.org/10.3171/spi.2007.6.2.133.
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Object Therapies that use bioactive materials as replacement extracellular matrices may hold the potential to mitigate the inhibition of regeneration observed after central nervous system trauma. Hyaluronic acid (HA), a nonsulfated glycosaminoglycan ubiquitous in all tissues, was investigated as a potential neural tissue engineering matrix. Methods Chick dorsal root ganglia were cultured in 3D hydrogel matrices composed of cross-linked thiol-modified HA or fibrin. Samples were cultured and images were acquired at 48-, 60-, and 192-hour time points. Images of all samples were analyzed at 48 hours of incubation to quantify the extent of neurite growth. Cultures in cross-linked thiolated HA exhibited more than a 50% increase in neurite length compared with fibrin samples. Furthermore, cross-linked thiolated HA supported neurites for the entire duration of the culture period, whereas fibrin cultures exhibited collapsed and degenerating extensions beyond 60 hours. Two concentrations of the thiolated HA (0.5 and 1%) were then placed at the site of a complete thoracic spinal cord transection in rats. The ability of the polymer to promote regeneration was tested using motor evoked potentials, retrograde axonal labeling, and behavioral assessments. There were no differences in any of the parameters between rats treated with the polymer and controls. Conclusions The use of a cross-linked HA scaffold promoted robust neurite outgrowth. Although there was no benefit from the polymer in a rodent spinal cord injury model, the findings in this study represent an early step in the development of semisynthetic extracellular matrice scaffolds for the treatment of neuronal injury.
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Hollis, Edmund R., Pouya Jamshidi, Karin Löw, Armin Blesch, and Mark H. Tuszynski. "Induction of corticospinal regeneration by lentiviral trkB-induced Erk activation." Proceedings of the National Academy of Sciences 106, no. 17 (April 9, 2009): 7215–20. http://dx.doi.org/10.1073/pnas.0810624106.
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Several experimental manipulations of the CNS environment successfully elicit regeneration of sensory and bulbospinal motor axons but fail to elicit regeneration of corticospinal axons, suggesting that cell-intrinsic mechanisms limit the regeneration of this critical class of motor neurons. We hypothesized that enhancement of intrinsic neuronal growth mechanisms would enable adult corticospinal motor axon regeneration. Lentiviral vectors were used to overexpress the BDNF receptor trkB in layer V corticospinal motor neurons. After subcortical axotomy, trkB transduction induced corticospinal axon regeneration into subcortical lesion sites expressing BDNF. In the absence of trkB overexpression, no regeneration occurred. Selective deletion of canonical, trkB-mediated neurite outgrowth signaling by mutation of the Shc/FRS-2 activation domain prohibited Erk activation and eliminated regeneration. These findings support the hypothesis that the refractory regenerative state of adult corticospinal axons can be attributed at least in part to neuron-intrinsic mechanisms, and that activation of ERK signaling can elicit corticospinal tract regeneration.
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Tone, S. Ong, Y. Z. Alabed, A. Di Polo, and A. E. Fournier. "INVESTIGATING CRMP4 FUNCTION IN NERVE REGENERATION." Clinical & Investigative Medicine 31, no. 4 (August 1, 2008): 18. http://dx.doi.org/10.25011/cim.v31i4.4818.
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Background: The failure of CNS neurons to spontaneously regenerate following injury can be partially attributed to the expression of neurite outgrowth inhibitory myelin associated inhibitors (MAIs). MAIs signal through a tripartite receptor complex to activate the cytosolic protein RhoA and influence cytoskeletal dynamics. RhoA antagonists promote neuronal survival and regeneration in animal models of nerve injury. However, RhoA's potential as a therapeutic target may be limited by its widespread roles in multiple cellular processes and cell types. In an attempt to discover more specific therapeutic targets to promote nerve regeneration, our lab identified the cytosolic phosphoprotein CRMP4b (Collapsin Response Mediator Protein 4b) as a protein that functionally interacts with RhoA to mediate neurite outgrowth inhibition. Blockade of the RhoA-CRMP4b interaction with a competitive peptide (C4RIP) attenuates myelin-dependent neurite outgrowth inhibition. Methods: We are currently investigating the in vivo roles of CRMP4in regeneration in an optic nerve injury model by developing a readily deliverable version of C4RIP. Results: Preliminary results suggest that overexpression of C4RIP in retinal ganglion cells by adeno-associated virus does not promote regeneration. However, studies investigating the ability of C4RIP to promote nerve regeneration into the optic nerve following stimulation of neurons into anactive growth state are currently in progress. Conclusion: Elucidating the role of CRMP4 in nerve regeneration may provide insight into the molecular mechanisms following nervous system injury and lead to the development of more specific therapeutic interventions. Reference: Alabed YZ, Pool M, Ong Tone S, Fournier AE.Identification of CRMP4 as a convergent regulator of axon outgrowth inhibition. J Neurosci 2007;27:1702-11.
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Gaublomme, Djoere, Tom Buyens, and Lieve Moons. "Automated Analysis of Neurite Outgrowth in Mouse Retinal Explants." Journal of Biomolecular Screening 18, no. 5 (December 27, 2012): 534–43. http://dx.doi.org/10.1177/1087057112471989.
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Despite intensive research efforts over the past years, regeneration of injured axons in the central nervous system remains elusive. In the quest for neurostimulatory agents that promote regeneration, well-defined models and analysis methods are required. Tissue explant cultures closely resemble the in vivo situation, making them ideal to study the effect of compounds on the neuro-glial network. This study reports the optimization of an explant culture technique using retinas of neonatal mice and the development of an analysis script that allows for rapid and automated analysis of neurite outgrowth from these explants. The key features of this script (i.e., local thresholding and form selection) allow for swift and unbiased detection of neurite outgrowth. The novel analysis method is compared with two commonly used manual methods and successfully validated by performing dose-response studies with molecules known to either inhibit (anti–β1-integrin antibody) or stimulate (brain-derived neurotrophic factor and ciliary neurotrophic factor) neurite outgrowth from retinal explants. Finally, the new analysis script is used to study whether retinal explant origin has any effect on neurite outgrowth.
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Lefcort, F., K. Venstrom, J. A. McDonald, and L. F. Reichardt. "Regulation of expression of fibronectin and its receptor, alpha 5 beta 1, during development and regeneration of peripheral nerve." Development 116, no. 3 (November 1, 1992): 767–82. http://dx.doi.org/10.1242/dev.116.3.767.
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The extracellular matrix glycoprotein, fibronectin, is a potent promoter of peripheral neurite outgrowth. Interactions of peripheral neurons with fibronectin have been shown to be primarily mediated by the beta 1 class of integrin heterodimers. In the present study, we have examined the expression and regulation of fibronectin and its integrin receptor, alpha 5 beta 1, in developing and regenerating chick peripheral nerve. We show that fibronectin and alpha 5 beta 1 are expressed at comparatively high levels in developing nerve with alpha 5 beta 1 expression on axons and non-neuronal cells. With nerve maturation, both proteins are less prominently expressed and the cellular pattern of alpha 5 beta 1 expression becomes more restricted. Following lesion of mature nerve, both fibronectin and alpha 5 beta 1 are strongly induced with prominent expression of alpha 5 beta 1 on regenerating neurites and Schwann cells. The elevation in fibronectin levels in the regenerating nerve is highest in the vicinity of the lesion, an area undergoing extensive cellular remodeling including Schwann cell migration and growth cone extension. Our results suggest that fibronectin and its receptor, alpha 5 beta 1, may mediate functionally important interactions in the development and regeneration of peripheral nerve.
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Hara, Koichi, Koichi Uchida, Atsushi Fukunaga, Yoshiaki Kuroshima, Motoyuki Yamada, and Takeshi Kawase. "Neurite Growth Capability of Rat Fetal Neuronal Cells against Matured CNS Myelin in Vitro." Cell Transplantation 9, no. 5 (September 2000): 717–24. http://dx.doi.org/10.1177/096368970000900521.
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Reconstruction of neurocircuits by transplanted cells is expected to become an effective therapy for brain damage. In order to establish the transplantation therapy, it is necessary to find transplantable cells capable of reconstructing the lesioned neurocircuitry. We have reported that the younger neuronal cells such as neural stem cells are useful transplant materials because of their vigorous capacity for forming abundant neurites. On the other hand, it was reported that myelin-associated neurite growth inhibitor prevents neurite regeneration. In this study, we used rat fetal neuronal cells to examine the neurite growth capacity in the presence of mature CNS myelin. Crude CNS myelin was prepared from the brains of adult Wistar rats using previously described procedures. Testing wells were precoated with poly-L-lysine and additionally by overnight drying of a suspension containing 0, 5, 10, 15, or 20 μg/cm2 of the crude myelin protein. On embryonic days 10, 12, 15, and 17 (E10, E12, E15, and E17) embryos were surgically removed, mesencephalic neural plates were dissected out from the E10 embryos, and midbrain cells were taken from the E12, E15, and E17 embryos. The neural plates and midbrain cells were placed on the myelin-coated wells. After 24 h of culture (72 h in the case of neural plates), the number of surviving cells and the length of the neurites were examined immunocytochemically using anti-neurofilament (NF) antibody. Neurite length was measured by image analyzer Luzex-F. The mesencephalic neural plate was able to grow neurites even on 20 μg/cm2 central myelin. Almost the same number of midbrain cells attached themselves to the wells without myelin in every culture obtained from various stages of embryos. The number of cells attached on the myelin-coated wells decreased with the concentration of myelin. The number of NF-positive cells was higher in cultures of materials obtained from older embryos than in cultures obtained from younger embryos. The younger cells grew longer neurites than the older cells in the myelin noncoated wells. Neurite growth was inhibited strongly when the concentration of the central myelin was 10 μg/cm2 or greater, but on the 5 μg/cm2 myelin, the younger the cells were, the longer neurites they had. When the length of the longest neurites in one field of the image analyzer was further examined in the same way, the younger the cells were, the longer their axons grew on 0 and 5 μg/cm2 myelin. Thus, CNS myelin was seen to be a significant inhibitor of the recovery of injured neural tissue of the adult CNS. Younger cells grew longer neurites than older cells on CNS myelin, and so it was suggested that neural stem cells or younger neurons may serve as tissue for transplantation therapy.
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Hashimoto, S. "K-252a, a potent protein kinase inhibitor, blocks nerve growth factor-induced neurite outgrowth and changes in the phosphorylation of proteins in PC12h cells." Journal of Cell Biology 107, no. 4 (October 1, 1988): 1531–39. http://dx.doi.org/10.1083/jcb.107.4.1531.
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Nerve growth factor (NGF) promotes neuronal differentiation of PC12 pheochromocytoma cells. One of the most prominent and distinguishing features of neuronal differentiation is neurite outgrowth. The mechanism by which NGF causes the cells to elaborate neurites is unknown. This study shows that K-252a, a potent protein kinase inhibitor, blocks NGF-induced neurite outgrowth and the changes in protein phosphorylation elicited by NGF. In the experiment with intact cells phosphorylated with 32P-orthophosphoric acid, an exposure of PC12h cells to NGF (50 ng/ml) caused an increase in the phosphorylation of tyrosine hydroxylase and a 35,000-D protein and a decrease in a 36,500-D protein. Pretreatment of PC12h cells with K-252a (100 nM) inhibited the effects of NGF on the phosphorylation of these three proteins. In the phosphorylation of cell-free extracts with [gamma-32P] ATP, treatment of PC12h cells with NGF (50 ng/ml) caused a decrease in the phosphorylation of Nsp100. Pretreatment of the cells with K-252a (30 nM) almost completely blocked the NGF effect on the phosphorylation of Nsp100 elicited by subsequent treatment of the cells with NGF. Treatment of PC12h cells with NGF promoted outgrowth of neurites. The addition of K-252a (100 nM) into the culture almost completely blocked the generation of neurites elicited by NGF. Earlier studies demonstrated that NGF-induced neurite outgrowth in PC12 cells involves at least two components: the first of these is transcription-dependent and the second is transcription-independent. To determine the component on which K-252a acts, experiments were carried out on NGF-induced priming or regeneration of neurites. When K-252a was present in the priming step, NGF induced only actinomycin D-sensitive neurites, showing that K-252a interferes with the transcription-dependent actions of NGF. When already primed cells were treated with NGF, actinomycin D-resistant neurites were formed and these were blocked by K-252a, showing that the inhibitor interferes with the transcription-independent actions of NGF as well. Although the exact mechanism of inhibition of NGF-promoted neurite formation by K-252a is unknown, the most probable explanation is that both transcription-dependent and -independent components are involved in at least one step of the activation of some specific protein kinase(s) that can be suppressed by K-252a.
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Onizuka, Shin, Mayumi Takasaki, and Naweed I. Syed. "Long-term Exposure to Local but Not Inhalation Anesthetics Affects Neurite Regeneration and Synapse Formation between Identified Lymnaea Neurons." Anesthesiology 102, no. 2 (February 1, 2005): 353–63. http://dx.doi.org/10.1097/00000542-200502000-00018.
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Background General and local anesthetics are used in various combinations during surgical procedures to repair damaged tissues and organs, which in almost all instances involve nervous system functions. Because synaptic transmission recovers rapidly from various inhalation anesthetics, it is generally assumed that their effects on nerve regeneration and synapse formation that precede injury or surgery may not be as detrimental as that of their local counterparts. However, a direct comparison of most commonly used inhalation (sevoflurane, isoflurane) and local anesthetics (lidocaine, bupivacaine), vis-a-vis their effects on synapse transmission, neurite regeneration, and synapse formation has not yet been performed. Methods In this study, using cell culture, electrophysiologic and imaging techniques on unequivocally identified presynaptic and postsynaptic neurons from the mollusc Lymnaea, the authors provided a comparative account of the effects of both general and local anesthetics on synaptic transmission, nerve regeneration, and synapse formation between cultured neurons. Results The data show that clinically used concentrations of both inhalation and local anesthetics affect synaptic transmission in a concentration-dependent and reversal manner. The authors provided the first direct evidence that long-term overnight treatment of cultured neurons with sevoflurane and isoflurane does not affect neurite regeneration, whereas both lidocaine and bupivacaine suppress neurite outgrowth completely. The soma-soma synapse model was then used to compare the effects of both types of agents on synapse formation. The authors found that local but not inhalation anesthetics drastically reduced the incidence of synapse formation. The local anesthetic-induced prevention of synapse formation most likely involved the failure of presynaptic machinery, which otherwise developed normally in the presence of both sevoflurane and isoflurane. Conclusion This study thus provides the first comparative, albeit preclinical, account of the effects of both general and local anesthetics on synaptic transmission, nerve regeneration, and synapse formation and demonstrates that clinically used lidocaine and bupivacaine have drastic long-term effects on neurite regeneration and synapse formation as compared with sevoflurane and isoflurane.
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Katiyar, Kritika S., Abraham Lin, Alexander Fridman, Carolyn E. Keating, D. Kacy Cullen, and Vandana Miller. "Non-Thermal Plasma Accelerates Astrocyte Regrowth and Neurite Regeneration Following Physical Trauma In Vitro." Applied Sciences 9, no. 18 (September 8, 2019): 3747. http://dx.doi.org/10.3390/app9183747.
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Non-thermal plasma (NTP), defined as a partially ionized gas, is an emerging technology with several biomedical applications, including tissue regeneration. In particular, NTP treatment has been shown to activate endogenous biological processes to promote cell regrowth, differentiation, and proliferation in multiple cell types. However, the effects of this therapy on nervous system regeneration have not yet been established. Accordingly, the current study explored the effects of a nanosecond-pulsed dielectric barrier discharge plasma on neural regeneration. Following mechanical trauma in vitro, plasma was applied either directly to (1) astrocytes alone, (2) neurons alone, or (3) neurons or astrocytes in a non-contact co-culture. Remarkably, we identified NTP treatment intensities that accelerated both neurite regeneration and astrocyte regrowth. In astrocyte cultures alone, an exposure of 20–90 mJ accelerated astrocyte re-growth up to three days post-injury, while neurons required lower treatment intensities (≤20 mJ) to achieve sub-lethal outgrowth. Following injury to neurons in non-contact co-culture with astrocytes, 20 mJ exposure of plasma to only neurons or astrocytes resulted in increased neurite regeneration at three days post-treatment compared to the untreated, but no enhancement was observed when both cell types were treated. At day seven, although regeneration further increased, NTP did not elicit a significant increase from the control. However, plasma exposure at higher intensities was found to be injurious, underscoring the need to optimize exposure levels. These results suggest that growth-promoting physiological responses may be elicited via properly calibrated NTP treatment to neurons and/or astrocytes. This could be exploited to accelerate neurite re-growth and modulate neuron-astrocyte interactions, thereby hastening nervous system regeneration.
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Rand, C. D., G. E. Spencer, and R. L. Carlone. "Retinoic acid as a chemoattractant for cultured embryonic spinal cord neurons of the African Clawed Frog, Xenopus laevis." Canadian Journal of Zoology 95, no. 9 (September 2017): 653–61. http://dx.doi.org/10.1139/cjz-2016-0279.
Full textAbstract:
Retinoic acid (RA), an active metabolite of vitamin A, is important for neural development and regeneration and can induce neurite outgrowth. It may also act as a guidance molecule by attracting neurite processes during outgrowth. In the African Clawed Frog (Xenopus laevis (Daudin, 1802)), RA has been shown to play an important role in the development of the anterior–posterior axis. However, whether RA can act as a trophic or tropic molecule on embryonic neurons of this species has not been determined. In this study, we investigated the effects of two retinoid isomers, all-trans retinoic acid (atRA) and 9-cis retinoic acid (9-cisRA), on cultured embryonic spinal cord neurons of X. laevis. Both isomers significantly enhanced neurite outgrowth compared with the vehicle control. In addition, atRA induced growth cone turning, which was blocked with a retinoic acid receptor (RAR) antagonist, selective for the β receptor subtype. Immunostaining also revealed RAR immunoreactivity in the neurites and growth cones of these cells. Interestingly, the 9-cisRA isomer also induced significant growth cone turning and this response was inhibited by a retinoid X receptor (RXR) pan-antagonist. Overall, we have provided evidence for both trophic and chemotropic actions of two naturally occurring retinoid isomers on Xenopus embryonic spinal cord neurons in culture.
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Clark, P., S. Britland, and P. Connolly. "Growth cone guidance and neuron morphology on micropatterned laminin surfaces." Journal of Cell Science 105, no. 1 (May 1, 1993): 203–12. http://dx.doi.org/10.1242/jcs.105.1.203.
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Neurite growth cones detect and respond to guidance cues in their local environment that determine stereotyped pathways during development and regeneration. Micropatterns of laminin (which was found to adsorb preferentially to photolithographically defined hydrophobic areas of micropatterns) were here used to model adhesive pathways that might influence neurite extension. The responses of growth cones were determined by the degree of guidance of neurite extension and also by examining growth cone morphology. These parameters were found to be strongly dependent on the geometry of the patterned laminin, and on neuron type. Decreasing the spacing of multiple parallel tracks of laminin alternating with non-adhesive tracks, resulted in decreased guidance of chick embryo brain neurons. Single isolated 2 microns tracks strongly guided neurite extension whereas 2 microns tracks forming a 4 microns period multiple parallel pattern did not. Growth cones appear to be capable of bridging the narrow non-adhesive tracks, rendering them insensitive to the smaller period multiple parallel adhesive patterns. These observations suggest that growth cones would be unresponsive to the multiple adhesive cues such as would be presented by oriented extracellular matrix or certain axon fascicle structures, but could be guided by isolated adhesive tracks. Growth cone morphology became progressively simpler on progressively narrower single tracks. On narrow period multiple parallel tracks (which did not guide neurite extension) growth cones spanned a number of adhesive/non-adhesive tracks, and their morphology suggests that lamellipodial advance may be independent of the substratum by using filopodia as a scaffold. In addition to acting as guidance cues, laminin micropatterns also appeared to influence the production of primary neurites and their subsequent branching. On planar substrata, dorsal root ganglion neurons were multipolar, with highly branched neurite outgrowth whereas, on 25 microns tracks, neurite branching was reduced or absent, and neuron morphology was typically bipolar. These observations indicate the precision with which growth cone advance may be controlled by substrata and suggest a role for patterned adhesiveness in neuronal morphological differentiation, but also highlight some of the limitations of growth cone sensitivity to substratum cues.
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Tone, Stephan Ong, Yazan Z. Alabed, and Alyson E. Fournier. "The role of CRMP4 in nerve regenerations." Clinical & Investigative Medicine 30, no. 4 (August 1, 2007): 91. http://dx.doi.org/10.25011/cim.v30i4.2869.
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The inability of CNS neurons to regenerate and reform functional connections following spinal cord injury has devastating clinical consequences. The failure of CNS neurons to spontaneously regenerate following injury can be partially attributed to the expression of neurite outgrowth inhibitory myelin associated inhibitors (MAIs). MAIs signal through a tripartite receptor complex to activate the cytosolic protein RhoA and influence cytoskeletal dynamics. RhoA antagonists promote neuronal survival and regeneration in animal models of nerve injury. However, RhoA's potential as a therapeutic target may be limited by its widespread roles in multiples cellular processes and cell types. In an attempt to discover more specific therapeutic targets to promote nerve regeneration, our lab identified the cytosolic phosphoprotein CRMP4b (Collapsin Response Mediator Protein 4b) as a protein that functionally interacts with RhoA to mediate neurite outgrowth inhibition. siRNA-mediated knockdown of CRMP4 and blockade of the RhoA-CRMP4b interaction with a competitive peptide (C4RIP) attenuates myelin-dependent neurite outgrowth inhibition. Analysis of the proximal tip of extending axons (growth cones) by time lapse video microscopy reveals that C4RIP regulates filopodial dynamics indicating that C4RIP modulates the actin cytoskeleton. We are currently investigating the in vivo roles of CRMP4 in regeneration in an optic nerve injury model by developing readily deliverable C4RIP and a CRMP4 knockout mouse. Elucidating the role of CRMP4 in nerve regeneration may provide insight into the molecular mechanisms following nervous system injury.
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Chen, Jieli, Alex Zacharek, Xu Cui, Amjad Shehadah, Hao Jiang, Cynthia Roberts, Mei Lu, and Michael Chopp. "Treatment of Stroke with a Synthetic Liver X Receptor Agonist, TO901317, Promotes Synaptic Plasticity and Axonal Regeneration in Mice." Journal of Cerebral Blood Flow & Metabolism 30, no. 1 (September 2, 2009): 102–9. http://dx.doi.org/10.1038/jcbfm.2009.187.
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In this study, we tested the hypothesis that TO901317 promotes synapse plasticity and axonal regeneration after stroke. Adult male C57BL/6J mice were subjected to middle cerebral artery occlusion (MCAo) and treated with or without TO901317 starting 24 h after MCAo daily for 14 days. Axonal damage and regeneration were evaluated by immunostaining. TO901317 significantly increased synaptophysin expression and axonal regeneration, as well as decreased the expressions of amyloid betaA4 precursor protein and Nogo receptor (NgR) in the ischemic brain. To test whether TO901317 regulates the phosphorylation of phosphatidylinositol 3-kinase (p-PI3K) and Akt (p-Akt) activity in the ischemic brain, MCAo mice were treated with or without TO901317 starting 24 h after MCAo daily for 4 days and were then killed at 5 days after MCAo. TO901317 treatment significantly increased p-PI3K and p-Akt activity, but did not increase total PI3K expression in the ischemic brain. Using primary cortical neuron (PCN) culture, TO901317 significantly increased synaptophysin expression, p-PI3K activity, and decreased NgR expression compared with nontreated controls. TO901317 also significantly increased neurite outgrowth, and inhibition of the PI3K/Akt pathway by LY294002 decreased neurite outgrowth in both controls and TO901317-treated groups in cultured hypoxic PCN. These data indicate that TO901317 promotes synaptic plasticity and axonal regeneration, and that PI3K/Akt signaling activity contributes to neurite outgrowth.
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Greene, L. A., S. A. Drexler, J. L. Connolly, A. Rukenstein, and S. H. Green. "Selective inhibition of responses to nerve growth factor and of microtubule-associated protein phosphorylation by activators of adenylate cyclase." Journal of Cell Biology 103, no. 5 (November 1, 1986): 1967–78. http://dx.doi.org/10.1083/jcb.103.5.1967.
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To study the influence of cAMP on cellular responses to nerve growth factor (NGF) and to use elevation of intracellular cAMP to probe the NGF mechanism, cultured PC12 pheochromocytoma cells were exposed to forskolin and cholera toxin. As in other cell types, the latter agents greatly increased PC12 cell cAMP levels. Such treatment also brought about a reversible, dose-dependent suppression of NGF-promoted regeneration of neurites. In support of the role of cAMP in this effect, regeneration blockage by forskolin was potentiated by phosphodiesterase inhibitors. When tested on NGF-stimulated initiation of process outgrowth, cholera toxin and forskolin exerted a dual effect. As in previous studies, these drugs, when applied along with NGF, significantly enhanced the initial formation of short cytoplasmic extensions. However, after approximately 3 d of NGF exposure, at which time such extensions begin to acquire the morphological and ultrastructural features of neurites, these agents suppressed process outgrowth. That is, the neurites were fewer in number, significantly less branched, and much shorter than in control cultures. Such changes also occurred when these drugs were added to cultures that had been pretreated with NGF alone. Whereas forskolin and cholera toxin affect the formation and regeneration of neurites, these drugs did not interfere with the short-latency, transient changes in surface morphology that are triggered by NGF, nor did they inhibit transcription-dependent priming. In contrast, the rapidly occurring NGF-induced phosphorylation of tyrosine hydroxylase was suppressed. Moreover, forskolin and cholera toxin rapidly and selectively blocked the NGF-promoted phosphorylation of a set of microtubule-associated proteins known as chartins. Previous observations have suggested a causal relationship between NGF-induced chartin microtubule-associated protein phosphorylation and the formation and outgrowth of neurites. This is supported by the present data and provides a possible mechanism whereby elevated cAMP may interfere with neurite growth and regeneration.
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Kastin, Abba, and Weihong Pan. "Targeting Neurite Growth Inhibitors to Induce CNS Regeneration." Current Pharmaceutical Design 11, no. 10 (April 1, 2005): 1247–53. http://dx.doi.org/10.2174/1381612053507440.
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Inoue, Hiroshi K. "The process of neurite formation and nerve regeneration." Neuroscience Research Supplements 3 (January 1986): S33. http://dx.doi.org/10.1016/0921-8696(86)90083-6.
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Pita-Thomas, Wolfgang, Manuel Nieto-Sampedro, Rodrigo M. Maza, and Manuel Nieto-Diaz. "Factors promoting neurite outgrowth during deer antler regeneration." Journal of Neuroscience Research 88, no. 14 (July 13, 2010): 3034–47. http://dx.doi.org/10.1002/jnr.22459.
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Zhang, Ping, and Shan Shan Wu. "Nanofibers/PVA Blended Nano Fibre Matrix for Nervous Tissue Regeneration." Applied Mechanics and Materials 404 (September 2013): 95–99. http://dx.doi.org/10.4028/www.scientific.net/amm.404.95.
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Nanofibers produced by electrospinning represent a new class of promising scaffolds to support nerve regeneration. Here, we found that the blended solutions of chitosan (CS) with Poly (vinyl alcohol) (PVA) are appropriate for electrospinning when they form conductive, unstructured fluids displaying plasticity, rather than elasticity, in the bulk and at the interface. We then studied that utilize electrospun nanofibers to manipulate biological processes relevant to nervous tissue regeneration, including stem cell differentiation, guidance of neurite extension, and peripheral nerve injury treatments. The main objective of this article is to provide valuable methods for investigating the mechanisms of neurite growth on novel nanofibrous scaffolds and optimization of the nanofiber scaffolds and conduits for repairing peripheral nerve injuries.
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Martín-López, Eduardo, Manuel Nieto-Díaz, and Manuel Nieto-Sampedro. "Differential Adhesiveness and Neurite-promoting Activity for Neural Cells of Chitosan, Gelatin, and Poly-l-Lysine Films." Journal of Biomaterials Applications 26, no. 7 (September 28, 2010): 791–809. http://dx.doi.org/10.1177/0885328210379928.
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Chitosan (Ch) and some of its derivatives have been proposed as good biomaterials for tissue engineering, to construct scaffolds promoting tissue regeneration. In this work we made composite films from Ch and mixtures of Ch with gelatin (G) and poly-l-lysine (PLL), and evaluated the growth on these films of PC12 and C6 lines as well as neurons and glial cells derived from cerebral tissue and dorsal root ganglia (DRG). C6 glioma cells proliferated on Ch, G, and Ch + G films, although metabolic activity was decreased by the presence of the G in the mixtures. NGF-differentiated PC12 cells, adhered preferentially on Ch and films containing PLL. Unlike NGF-treated PC12 cells, cortical and hippocampal neurons showed good adhesion to Ch and Ch + G films, where they extended neurites. Astrocytes adhered on Ch, Ch + G, and Ch + PLL mixtures, although viability decreased during the culture time. Olfactory ensheathing cells (OEC) adhered and proliferated to confluency on the wells covered with Ch + G films. Neurites from DRGs exhibited high extension on these films. These results demonstrate that Ch + G films have excellent adhesive properties for both neurons and regeneration-promoting glia (OEC). These films also promoted neurite extension from DRG, making them good candidates for tissue engineering of nerve repair.
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Okur, Zeynep, Oya I. Senturk, Canelif Yilmaz, Gulcihan Gulseren, Busra Mammadov, Mustafa O. Guler, and Ayse B. Tekinay. "Promotion of neurite outgrowth by rationally designed NGF-β binding peptide nanofibers." Biomaterials Science 6, no. 7 (2018): 1777–90. http://dx.doi.org/10.1039/c8bm00311d.
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Van Hooff, C. O., J. C. Holthuis, A. B. Oestreicher, J. Boonstra, P. N. De Graan, and W. H. Gispen. "Nerve growth factor-induced changes in the intracellular localization of the protein kinase C substrate B-50 in pheochromocytoma PC12 cells." Journal of Cell Biology 108, no. 3 (March 1, 1989): 1115–25. http://dx.doi.org/10.1083/jcb.108.3.1115.
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High levels of the neuron-specific protein kinase C substrate, B-50 (= GAP43), are present in neurites and growth cones during neuronal development and regeneration. This suggests a hitherto nonelucidated role of this protein in neurite outgrowth. Comparable high levels of B-50 arise in the pheochromocytoma PC12 cell line during neurite formation. To get insight in the putative growth-associated function of B-50, we compared its ultrastructural localization in naive PC12 cells with its distribution in nerve growth factor (NGF)- or dibutyryl cyclic AMP (dbcAMP)-treated PC12 cells. B-50 immunogold labeling of cryosections of untreated PC12 cells is mainly associated with lysosomal structures, including multivesicular bodies, secondary lysosomes, and Golgi apparatus. The plasma membrane is virtually devoid of label. However, after 48-h NGF treatment of the cells, B-50 immunoreactivity is most pronounced on the plasma membrane. Highest B-50 immunoreactivity is observed on plasma membranes surrounding sprouting microvilli, lamellipodia, and filopodia. Outgrowing neurites are scattered with B-50 labeling, which is partially associated with chromaffin granules. In NGF-differentiated PC12 cells, B-50 immunoreactivity is, as in untreated cells, also associated with organelles of the lysosomal family and Golgi stacks. B-50 distribution in dbcAMP-differentiated cells closely resembles that in NGF-treated cells. The altered distribution of B-50 immunoreactivity induced by differentiating agents indicates a shift of the B-50 protein towards the plasma membrane. This translocation accompanies the acquisition of neuronal features of PC12 cells and points to a neurite growth-associated role for B-50, performed at the plasma membrane at the site of protrusion.
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Teleanu, Raluca Ioana, Oana Gherasim, Tudor George Gherasim, Valentina Grumezescu, Alexandru Mihai Grumezescu, and Daniel Mihai Teleanu. "Nanomaterial-Based Approaches for Neural Regeneration." Pharmaceutics 11, no. 6 (June 8, 2019): 266. http://dx.doi.org/10.3390/pharmaceutics11060266.
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Mechanical, thermal, chemical, or ischemic injury of the central or peripheral nervous system results in neuron loss, neurite damage, and/or neuronal dysfunction, almost always accompanied by sensorimotor impairment which alters the patient’s life quality. The regenerative strategies for the injured nervous system are currently limited and mainly allow partial functional recovery, so it is necessary to develop new and effective approaches for nervous tissue regenerative therapy. Nanomaterials based on inorganic or organic and composite or hybrid compounds with tunable physicochemical properties and functionality proved beneficial for the transport and delivery/release of various neuroregenerative-relevant biomolecules or cells. Within the following paragraphs, we will emphasize that nanomaterial-based strategies (including nanosized and nanostructured biomaterials) represent a promising alternative towards repairing and regenerating the injured nervous system.
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Wang, Dong, Yanping Chen, Mingwen Liu, Qianqian Cao, Qihui Wang, Shuoshuo Zhou, Yaxian Wang, et al. "The long noncoding RNA Arrl1 inhibits neurite outgrowth by functioning as a competing endogenous RNA during neuronal regeneration in rats." Journal of Biological Chemistry 295, no. 25 (April 26, 2020): 8374–86. http://dx.doi.org/10.1074/jbc.ra119.011917.
Full textAbstract:
The intrinsic regeneration ability of neurons is a pivotal factor in the repair of peripheral nerve injury. Therefore, identifying the key modulators of nerve regeneration may help improve axon regeneration and functional recovery after injury. Unlike for classical transcription factors and regeneration-associated genes, the function of long noncoding RNAs (lncRNAs) in the regulation of neuronal regeneration remains mostly unknown. In this study, we used RNA-Seq–based transcriptome profiling to analyze the expression patterns of lncRNAs and mRNAs in rat dorsal root ganglion (DRG) following sciatic nerve injury. Analyses using the lncRNA-mRNA co-expression network, gene ontology enrichment, and Kyoto Encyclopedia of Genes and Genomes pathway databases indicated that the lncRNA Arrl1 decreases neurite outgrowth after neuronal injury. shRNA-mediated Arrl1 silencing increased axon regeneration both in vitro and in vivo and improved functional recovery of the sciatic nerve. Moreover, inhibiting an identified target gene of Arrl1, cyclin-dependent kinase inhibitor 2B (Cdkn2b), markedly promoted neurite outgrowth of DRG neurons. We also found that Arrl1 acts as a competing endogenous RNA that sponges a Cdkn2b repressor, microRNA-761 (miR-761), and thereby up-regulates Cdkn2b expression during neuron regeneration. We conclude that the lncRNA Arrl1 affects the intrinsic regeneration of DRG neurons by derepressing Cdkn2b expression. Our findings indicate a role for an lncRNA-microRNA-kinase pathway in the regulation of axon regeneration and functional recovery following peripheral nerve injury in rats.
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Roloff, Frank, Sarah Strauß, Peter M. Vogt, Gerd Bicker, and Christine Radtke. "Spider Silk as Guiding Biomaterial for Human Model Neurons." BioMed Research International 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/906819.
Full textAbstract:
Over the last years, a number of therapeutic strategies have emerged to promote axonal regeneration. An attractive strategy is the implantation of biodegradable and nonimmunogenic artificial scaffolds into injured peripheral nerves. In previous studies, transplantation of decellularized veins filled with spider silk for bridging critical size nerve defects resulted in axonal regeneration and remyelination by invading endogenous Schwann cells. Detailed interaction of elongating neurons and the spider silk as guidance material is unknown. To visualize direct cellular interactions between spider silk and neuronsin vitro, we developed anin vitrocrossed silk fiber array. Here, we describe in detail for the first time that human (NT2) model neurons attach to silk scaffolds. Extending neurites can bridge gaps between single silk fibers and elongate afterwards on the neighboring fiber. Culturing human neurons on the silk arrays led to an increasing migration and adhesion of neuronal cell bodies to the spider silk fibers. Within three to four weeks, clustered somata and extending neurites formed ganglion-like cell structures. Microscopic imaging of human neurons on the crossed fiber arraysin vitrowill allow for a more efficient development of methods to maximize cell adhesion and neurite growth on spider silk prior to transplantation studies.
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Wan, Rou, Arif Hussain, Atta Behfar, Steven L. Moran, and Chunfeng Zhao. "The Therapeutic Potential of Exosomes in Soft Tissue Repair and Regeneration." International Journal of Molecular Sciences 23, no. 7 (March 31, 2022): 3869. http://dx.doi.org/10.3390/ijms23073869.
Full textAbstract:
Soft tissue defects are common following trauma and tumor extirpation. These injuries can result in poor functional recovery and lead to a diminished quality of life. The healing of skin and muscle is a complex process that, at present, leads to incomplete recovery and scarring. Regenerative medicine may offer the opportunity to improve the healing process and functional outcomes. Barriers to regenerative strategies have included cost, regulatory hurdles, and the need for cell-based therapies. In recent years, exosomes, or extracellular vesicles, have gained tremendous attention in the field of soft tissue repair and regeneration. These nanosized extracellular particles (30–140 nm) can break the cellular boundaries, as well as facilitate intracellular signal delivery in various regenerative physiologic and pathologic processes. Existing studies have established the potential of exosomes in regenerating tendons, skeletal muscles, and peripheral nerves through different mechanisms, including promoting myogenesis, increasing tenocyte differentiation and enhancing neurite outgrowth, and the proliferation of Schwann cells. These exosomes can be stored for immediate use in the operating room, and can be produced cost efficiently. In this article, we critically review the current advances of exosomes in soft tissue (tendons, skeletal muscles, and peripheral nerves) healing. Additionally, new directions for clinical applications in the future will be discussed.
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Yang, Zhiyou, Baiping Liu, Long-en Yang, and Cai Zhang. "Platycodigenin as Potential Drug Candidate for Alzheimer’s Disease via Modulating Microglial Polarization and Neurite Regeneration." Molecules 24, no. 18 (September 4, 2019): 3207. http://dx.doi.org/10.3390/molecules24183207.
Full textAbstract:
Neuroinflammatory microenvironment, regulating neurite regrowth and neuronal survival, plays a critical role in Alzheimer’s disease (AD). During neuroinflammation, microglia are activated, inducing the release of inflammatory or anti-inflammatory factors depending on their polarization into classical M1 microglia or alternative M2 phenotype. Therefore, optimizing brain microenvironment by small molecule-targeted microglia polarization and promoting neurite regeneration might be a potential therapeutic strategy for AD. In this study, we found platycodigenin, a naturally occurring triterpenoid, promoted M2 polarization and inhibited M1 polarization in lipopolysaccharide (LPS)-stimulated BV2 and primary microglia. Platycodigenin downregulated pro-inflammatory molecules such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6 and nitric oxide (NO), while upregulated anti-inflammatory cytokine IL-10. Further investigation confirmed that platycodigenin inhibited cyclooxygenase-2 (Cox2) positive M1 but increased Ym1/2 positive M2 microglial polarization in primary microglia. In addition, platycodigenin significantly decreased LPS-induced the hyperphosphorylation of mitogen-activated protein kinase (MAPK) p38 and nuclear factor-κB (NF-κB) p65 subunits. Furthermore, the inactivation of peroxisome proliferators-activated receptor γ (PPARγ) induced by LPS was completely ameliorated by platycodigenin. Platycodigenin also promoted neurite regeneration and neuronal survival after Aβ treatment in primary cortical neurons. Taken together, our study for the first time clarified that platycodigenin effectively ameliorated LPS-induced inflammation and Aβ-induced neurite atrophy and neuronal death.
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Kim, Yu Mi, Jin Gao, Blaine Zern, and Ya Dong Wang. "Biofunctional Materials for Nerve Regeneration." Materials Science Forum 539-543 (March 2007): 547–50. http://dx.doi.org/10.4028/www.scientific.net/msf.539-543.547.
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Most biomaterials widely used in nerve regeneration are either inert or modified with ECM proteins or their epitopes. Neurotransmitters play a key role in neuronal development and function. Thus we decided to investigate the feasibility of using neurotransmitters to create biofunctional materials that actively engage nerve cells to achieve functional restoration after injury of the nervous system. Our data indicated that a properly designed biodegradable polymer with dopamine functional groups was more capable of promoting neurite growth. Such biofunctional materials can potentially provide a new strategy for nerve regeneration.
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Jeon, Kye-Im, and Krystel R. Huxlin. "How scars shape the neural landscape: Key molecular mediators of TGF-β1’s anti-neuritogenic effects." PLOS ONE 15, no. 11 (November 24, 2020): e0234950. http://dx.doi.org/10.1371/journal.pone.0234950.
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Following injury to the peripheral and central nervous systems, tissue levels of transforming growth factor (TGF)-β1 often increase, which is key for wound healing and scarring. However, active wound regions and scars appear to inhibit process outgrowth by regenerating neurons. We recently showed that corneal wound myofibroblasts block corneal nerve regeneration in vivo, and sensory neurite outgrowth in vitro in a manner that relies critically on TGF-β1. In turn, delayed, abnormal re-innervation contributes to long-term sensory dysfunctions of the ocular surface. Here, we exposed morphologically and biochemically-differentiated sensory neurons from the ND7/23 cell line to TGF-β1 to identify the intracellular signals regulating these anti-neuritogenic effects, contrasting them with those of Semaphorin(Sema)3A, a known inhibitor of neurite outgrowth. Neuronal morphology was quantified using phase-contrast imaging. Western blotting and specific inhibitors were then used to identify key molecular mediators. Differentiated ND7/23 cells expressed neuron-specific markers, including those involved in neurite extension and polarization. TGF-β1 increased phosphorylation of collapsin response mediator protein-2 (CRMP2), a molecule that is key for neurite extension. We now show that both glycogen synthase kinase (GSK)-3β and Smad3 modulate phosphorylation of CRMP2 after treatment with TGF-β1. GSK-3β appeared to exert a particularly strong effect, which could be explained by its ability to phosphorylate not only CRMP2, but also Smad3. In conclusion, TGF-β1’s inhibition of neurite outgrowth in sensory neurons appears to be regulated through a highly-conserved signaling pathway, which involves the GSK-3β/CRMP-2 loop via both canonical and non-canonical mechanisms. It is hoped that by defining the signaling pathways that control neurite outgrowth in wound environments, it will become possible to identify optimal molecular targets to promote re-innervation following injury.
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He, John Cijiang, Susana R. Neves, J. Dedrick Jordan, and Ravi Iyengar. "Role of the Go/i signaling network in the regulation of neurite outgrowthThis paper is one of a selection of papers published in this Special issue, entitled Second Messengers and Phosphoproteins—12th International Conference." Canadian Journal of Physiology and Pharmacology 84, no. 7 (July 2006): 687–94. http://dx.doi.org/10.1139/y06-025.
Full textAbstract:
Neurite outgrowth is a complex differentiation process stimulated by many neuronal growth factors and transmitters and by electrical activity. Among these stimuli are ligands for G-protein-coupled receptors (GPCR) that function as neurotransmitters. The pathways involved in GPCR-triggered neurite outgrowth are not fully understood. Many of these receptors couple to Gαo, one of the most abundant proteins in the neuronal growth cones. We have studied the Go signaling network involved in neurite outgrowth in Neuro2A cells. Gαo can induce neurite outgrowth. The CB1 cannabinoid receptor, a Go/i-coupled receptor expressed endogenously in Neuro2A cells, triggers neurite outgrowth by activating Rap1, which promotes the Gαo-stimulated proteasomal degradation of Rap1GAPII. CB1-receptor-mediated Rap1 activation leads to the activation of a signaling network that includes the small guanosine triphosphate (GTP)ases Ral and Rac, the protein kinases Src, and c-Jun N-terminal kinase (JNK), which converge onto the activation of signal transducer and activator of transcription 3 (Stat3), a key transcription factor that mediates the gene expression process of neurite outgrowth in Neuro2A cells. This review describes current findings from our laboratory and also discusses alternative pathways that Go/i might mediate to trigger neurite outgrowth. We also analyze the role neurotransmitters, which stimulate Go/i to activate a complex signaling network controlling neurite outgrowth, play in regeneration after neuronal injury.