Generic placeholder image

CNS & Neurological Disorders - Drug Targets

Author(s): Xianbin Wang, Wei Ma, Tongtong Wang, Jinwei Yang, Zhen Wu, Kuangpin Liu, Yunfei Dai, Chenghao Zang, Wei Liu, Jie Liu, Yu Liang, Jianhui Guo* and Liyan Li*

DOI: 10.2174/1871527319666200117110056

DownloadDownload PDF Flyer Cite As
BDNF-TrkB and proBDNF-p75NTR/Sortilin Signaling Pathways are Involved in Mitochondria-Mediated Neuronal Apoptosis in Dorsal Root Ganglia after Sciatic Nerve Transection

Page: [66 - 82] Pages: 17

  • * (Excluding Mailing and Handling)

Abstract

Background: Brain-Derived Neurotrophic Factor (BDNF) plays critical roles during development of the central and peripheral nervous systems, as well as in neuronal survival after injury. Although proBDNF induces neuronal apoptosis after injury in vivo, whether it can also act as a death factor in vitro and in vivo under physiological conditions and after nerve injury, as well as its mechanism of inducing apoptosis, is still unclear.

Objective: In this study, we investigated the mechanisms by which proBDNF causes apoptosis in sensory neurons and Satellite Glial Cells (SGCs) in Dorsal Root Ganglia (DRG) After Sciatic Nerve Transection (SNT).

Methods: SGCs cultures were prepared and a scratch model was established to analyze the role of proBDNF in sensory neurons and SGCs in DRG following SNT. Following treatment with proBDNF antiserum, TUNEL and immunohistochemistry staining were used to detect the expression of Glial Fibrillary Acidic Protein (GFAP) and Calcitonin Gene-Related Peptide (CGRP) in DRG tissue; immunocytochemistry and Cell Counting Kit-8 (CCK8) assay were used to detect GFAP expression and cell viability of SGCs, respectively. RT-qPCR, western blot, and ELISA were used to measure mRNA and protein levels, respectively, of key factors in BDNF-TrkB, proBDNF-p75NTR/sortilin, and apoptosis signaling pathways.

Results: proBDNF induced mitochondrial apoptosis of SGCs and neurons by modulating BDNF-TrkB and proBDNF-p75NTR/sortilin signaling pathways. In addition, neuroprotection was achieved by inhibiting the biological activity of endogenous proBDNF protein by injection of anti-proBDNF serum. Furthermore, the anti-proBDNF serum inhibited the activation of SGCs and promoted their proliferation.

Conclusion: proBDNF induced apoptosis in SGCs and sensory neurons in DRG following SNT. The proBDNF signaling pathway is a potential novel therapeutic target for reducing sensory neuron and SGCs loss following peripheral nerve injury.

Keywords: proBDNF, sciatic nerve transection, dorsal root ganglia, TrkB, p75NTR, sortilin, sensory neurons.

Graphical Abstract

[1]
Hu, P.; McLachlan, E.M. Selective reactions of cutaneous and muscle afferent neurons to peripheral nerve transection in rats. J. Neurosci., 2003, 23(33), 10559-67.
[2]
Barbizan, R.; Castro, M.V.; Rodrigues, A.C.; Barraviera, B.; Ferreira, R.S.; Oliveira, A.L. Motor recovery and synaptic preservation after ventral root avulsion and repair with a fibrin sealant derived from snake venom. PLoS One, 2013, 8(5)e63260
[http://dx.doi.org/10.1371/journal.pone.0063260] [PMID: 23667596]
[3]
Masgutov, R.F.; Masgutova, G.A.; Zhuravleva, M.N. Human adipose-derived stem cells stimulate neuroregeneration. Clin. Exp. Med., 2016, 16(3), 451-61.
[http://dx.doi.org/10.1007/s10238-015-0364-3] [PMID: 26047869]
[4]
Araújo, M.R.; Kyrylenko, S.; Spejo, A.B. Transgenic human embryonic stem cells overexpressing FGF2 stimulate neuroprotection following spinal cord ventral root avulsion. Exp. Neurol., 2017, 294, 45-57.
[http://dx.doi.org/10.1016/j.expneurol.2017.04.009] [PMID: 28450050]
[5]
Nho, B.; Lee, J.; Lee, J.; Ko, K.R.; Lee, S.J.; Kim, S. Effective control of neuropathic pain by transient expression of hepatocyte growth factor in a mouse chronic constriction injury model. FASEB J., 2018, 32(9), 5119-31.
[http://dx.doi.org/10.1096/fj.201800476R] [PMID: 29913557]
[6]
Li, M.; Zhu, Y.; Peng, W.; Wang, H.; Yuan, Y.; Gu, X. Achyranthes bidentata polypeptide protects schwann cells from apoptosis in hydrogen peroxide-induced oxidative stress. Front. Neurosci., 2018, 12, 868.
[http://dx.doi.org/10.3389/fnins.2018.00868] [PMID: 30555292]
[7]
Perez, M.; Cartarozzi, L.P.; Chiarotto, G.B.; Oliveira, S.A.; Guimarães, F.S.; Oliveira, A.L.R. Neuronal preservation and reactive gliosis attenuation following neonatal sciatic nerve axotomy by a fluorinated cannabidiol derivative. Neuropharmacology, 2018, 140, 201-8.
[http://dx.doi.org/10.1016/j.neuropharm.2018.08.009] [PMID: 30096328]
[8]
Pius-Sadowska, E.; Machaliński, B. BDNF - A key player in cardiovascular system. J. Mol. Cell. Cardiol., 2017, 110, 54-60.
[http://dx.doi.org/10.1016/j.yjmcc.2017.07.007] [PMID: 28736262]
[9]
Song, M.; Martinowich, K.; Lee, F.S. BDNF at the synapse: why location matters. Mol. Psychiatry, 2017, 22(10), 1370-75.
[http://dx.doi.org/10.1038/mp.2017.144] [PMID: 28937692]
[10]
Chen, T.; Yu, Y.; Tang, L.J. Neural stem cells over-expressing brain-derived neurotrophic factor promote neuronal survival and cytoskeletal protein expression in traumatic brain injury sites. Neural Regen. Res., 2017, 12(3), 433-9.
[11]
Kojima, M.; Mizui, T. BDNF propeptide: a novel modulator of synaptic plasticity. Vitam. Horm., 2017, 104, 19-28.
[http://dx.doi.org/10.1016/bs.vh.2016.11.006] [PMID: 28215295]
[12]
Leal, G.; Bramham, C.R.; Duarte, C.B. BDNF and hippocampal synaptic plasticity. Vitam. Horm., 2017, 104, 153-95.
[http://dx.doi.org/10.1016/bs.vh.2016.10.004] [PMID: 28215294]
[13]
Campos, C.; Rocha, NBF.; Lattari, E. Exercise induced neuroplasticity to enhance therapeutic outcomes of cognitive remediation in schizophrenia: analyzing the role of brain-derived neurotrophic factor.CNS Neurol Disord Drug Targets, 2017, 16(6), 638-51.
[http://dx.doi.org/10.2174/1871527315666161223142918] [PMID: 28017130]
[14]
Huang, E.J.; Reichardt, L.F. Trk receptors: roles in neuronal signal transduction. Annu. Rev. Biochem., 2003, 72(1), 609-42.
[http://dx.doi.org/10.1146/annurev.biochem.72.121801.161629] [PMID: 12676795]
[15]
Je, H.S.; Yang, F.; Ji, Y.; Nagappan, G.; Hempstead, B.L.; Lu, B. Role of pro-brain-derived neurotrophic factor (proBDNF) to mature BDNF conversion in activity-dependent competition at developing neuromuscular synapses. Proc. Natl. Acad. Sci. USA, 2012, 109(39), 15924-9.
[http://dx.doi.org/10.1073/pnas.1207767109] [PMID: 23019376]
[16]
Luo, L.; Li, C.; Du, X. Effect of aerobic exercise on BDNF/proBDNF expression in the ischemic hippocampus and depression recovery of rats after stroke. Behav. Brain Res., 2018.
[PMID: 30500428]
[17]
Kenchappa Rajappa S, Zampieri Niccolò, Chao Moses V, et al.Ligand-dependent cleavage of the P75 neurotrophin receptor is necessary for NRIF nuclear translocation and apoptosis in sympathetic neurons 2006, 50(2), 219-32.
[http://dx.doi.org/10.1016/j.neuron.2006.03.011]
[18]
Teng, HK. Teng KK, Lee R, et al.ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J. Neurosci., 2005, 25(22), 5455-63.
[http://dx.doi.org/10.1523/JNEUROSCI.5123-04.2005] [PMID: 15930396]
[19]
Fleitas, C.; Piñol-Ripoll, G.; Marfull, P. proBDNF is modified by advanced glycation end products in Alzheimer’s disease and causes neuronal apoptosis by inducing p75 neurotrophin receptor processing. Mol. Brain, 2018, 11(1), 68.
[http://dx.doi.org/10.1186/s13041-018-0411-6] [PMID: 30428894]
[20]
Liu, S.; Guo, W.; Zhou, H. proBDNF inhibits the proliferation and migration of OLN‑93 oligodendrocytes. Mol. Med. Rep., 2018, 18(4), 3809-3817.
[http://dx.doi.org/10.3892/mmr.2018.9407] [PMID: 30132570]
[21]
Li, X.T.; Liang, Z.; Wang, TT. Brain-derived neurotrophic factor promotes growth of neurons and neural stem cells possibly by triggering the phosphoinositide 3-kinase/AKT/glycogen synthase kinase-3β /β-catenin pathway. CNS Neurol. Disord. Drug Targets, 2017, 16(7), 828-836.
[http://dx.doi.org/10.2174/1871527316666170518170422] [PMID: 28524001]
[22]
Wang, X-B.; Ma, W.; Luo, T. A novel primary culture method for high-purity satellite glial cells derived from rat dorsal root ganglion. Neural Regen. Res., 2019, 14(2), 339-45.
[http://dx.doi.org/10.4103/1673-5374.244797] [PMID: 30531018]
[23]
Liang, C.C.; Park, A.Y.; Guan, J.L. In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat. Protoc., 2007, 2(2), 329-333.
[http://dx.doi.org/10.1038/nprot.2007.30] [PMID: 17406593]
[24]
Lu, X.; Xue, P.; Fu, L. HAX1 is associated with neuronal apoptosis and astrocyte proliferation after spinal cord injury. Tissue Cell, 2018, 54, 1-9.
[http://dx.doi.org/10.1016/j.tice.2018.07.001] [PMID: 30309497]
[25]
Feldman, A.T.; Wolfe, D. Tissue processing and hematoxylin and eosin staining. Methods Mol. Biol., 2014, 1180, 31-43.
[http://dx.doi.org/10.1007/978-1-4939-1050-2_3] [PMID: 25015141]
[26]
Kim, J.H.; Skates, S.J.; Uede, T. Osteopontin as a potential diagnostic biomarker for ovarian cancer. JAMA, 2002, 287(13), 1671-1679.
[27]
Li, D.; Yan, Y.; Yu, L.; Duan, Y. Procaine attenuates pain behaviors of neuropathic pain model rats possibly via inhibiting JAK2/STAT3. Biomol. Ther. (Seoul), 2016, 24(5), 489-94.
[http://dx.doi.org/10.4062/biomolther.2016.006] [PMID: 27530113]
[28]
Ormstad, H.; Bryn, V.; Verkerk, R. Serum tryptophan, tryptophan catabolites and brain-derived neurotrophic factor in subgroups of youngsters with autism spectrum disorders. CNS Neurol. Disord. Drug Targets, 2018, 17(8), 626-39.
[http://dx.doi.org/10.2174/1871527317666180720163221] [PMID: 30033880]
[29]
Unsain, N.; Nuñez, N.; Anastasía, A.; Mascó, D.H. Status epilepticus induces a TrkB to p75 neurotrophin receptor switch and increases brain-derived neurotrophic factor interaction with p75 neurotrophin receptor: an initial event in neuronal injury induction. Neuroscience, 2008, 154(3), 978-93.
[http://dx.doi.org/10.1016/j.neuroscience.2008.04.038] [PMID: 18511210]
[30]
Montroull, L.E.; Danelon, V.; Cragnolini, A.B.; Mascó, D.H. Loss of TrkB signaling due to status epilepticus induces a proBDNF-dependent cell death. Front. Cell. Neurosci., 2019, 13, 4.
[http://dx.doi.org/10.3389/fncel.2019.00004] [PMID: 30800056]
[31]
Davey, F.; Davies, A.M. TrkB signalling inhibits p75-mediated apoptosis induced by nerve growth factor in embryonic proprioceptive neurons. Curr. Biol., 1998, 8(16), 915-8.
[http://dx.doi.org/10.1016/S0960-9822(07)00371-5] [PMID: 9707403]
[32]
Friedman, W.J. Neurotrophins induce death of hippocampal neurons via the p75 receptor. J. Neurosci., 2000, 20(17), 6340-6.
[http://dx.doi.org/10.1523/JNEUROSCI.20-17-06340.2000] [PMID: 10964939]
[33]
Diniz, C.R.A.F.; Casarotto, P.C.; Resstel, L.; Joca, S.R.L. Beyond good and evil: A putative continuum-sorting hypothesis for the functional role of proBDNF/BDNF-propeptide/mBDNF in antidepressant treatment. Neurosci. Biobehav. Rev., 2018, 90, 70-83.
[http://dx.doi.org/10.1016/j.neubiorev.2018.04.001] [PMID: 29626490]
[34]
Liu, H.; Zhao, L.; Gu, W. Activation of satellite glial cells in trigeminal ganglion following dental injury and inflammation. J. Mol. Histol., 2018, 49(3), 257-63.
[http://dx.doi.org/10.1007/s10735-018-9765-4] [PMID: 29516260]
[35]
Wang, S.; Wang, Z.; Li, L. P2Y12 shRNA treatment decreases SGC activation to relieve diabetic neuropathic pain in type 2 diabetes mellitus rats. J. Cell. Physiol., 2018, 233(12), 9620-8.
[http://dx.doi.org/10.1002/jcp.26867] [PMID: 29943819]
[36]
Lim, H.; Lee, H.; Noh, K.; Lee, S.J. IKK/NF-κB-dependent satellite glia activation induces spinal cord microglia activation and neuropathic pain after nerve injury. Pain, 2017, 158(9), 1666-77.
[http://dx.doi.org/10.1097/j.pain.0000000000000959] [PMID: 28722693]
[37]
Mikuzuki, L.; Saito, H.; Katagiri, A. Phenotypic change in trigeminal ganglion neurons associated with satellite cell activation via extracellular signal-regulated kinase phosphorylation is involved in lingual neuropathic pain. Eur. J. Neurosci., 2017, 46(6), 2190-2202.
[http://dx.doi.org/10.1111/ejn.13667] [PMID: 28834578]
[38]
Wong, I.; Liao, H.; Bai, X. ProBDNF inhibits infiltration of ED1+ macrophages after spinal cord injury. Brain Behav. Immun., 2010, 24(4), 585-7.
[http://dx.doi.org/10.1016/j.bbi.2010.01.001] [PMID: 20083190]
[39]
Xu, Z.Q.; Sun, Y.; Li, H.Y.; Lim, Y.; Zhong, J.H.; Zhou, X.F. Endogenous proBDNF is a negative regulator of migration of cerebellar granule cells in neonatal mice. Eur. J. Neurosci., 2011, 33(8), 1376-1384.
[http://dx.doi.org/10.1111/j.1460-9568.2011.07635.x] [PMID: 21366730]
[40]
VonDran, M.W.; Singh, H.; Honeywell, J.Z.; Dreyfus, C.F. Levels of BDNF impact oligodendrocyte lineage cells following a cuprizone lesion. J. Neurosci., 2011, 31(40), 14182-90.
[http://dx.doi.org/10.1523/JNEUROSCI.6595-10.2011] [PMID: 21976503]
[41]
Xu, Z.Q.; Li, J.; Deng, J.; Jiang, X.J.; Zhou, H.D. [Effects of proBDNF on cell proliferation and differentiation in hippocampal dentate gyrus in Alzheimer’ disease rat model]. Zhonghua Yi Xue Za Zhi, 2010, 90(19), 1353-6.
[PMID: 20646587]
[42]
Orefice, L.L.; Shih, C.C.; Xu, H.; Waterhouse, E.G.; Xu, B. Control of spine maturation and pruning through proBDNF synthesized and released in dendrites. Mol. Cell. Neurosci., 2016, 71, 66-79.
[http://dx.doi.org/10.1016/j.mcn.2015.12.010] [PMID: 26705735]
[43]
Hanani, M. Satellite glial cells in sympathetic and parasympathetic ganglia: in search of function. Brain Res. Brain Res. Rev., 2010, 64(2), 304-27.
[http://dx.doi.org/10.1016/j.brainresrev.2010.04.009] [PMID: 20441777]
[44]
Liu, S.; Guo, W. Zhou H, et al.proBDNF inhibits the proliferation and migration of OLN‑93 oligodendrocytes. Mol. Med. Rep., 2018, 18(4), 3809-17.
[45]
Zhou, L.; Xiong, J. , Ruan C-S, et al.ProBDNF/p75NTR/sortilin pathway is activated in peripheral blood of patients with alcohol dependence. Transl. Psychiatry, 2018, 7(11), 2.
[http://dx.doi.org/10.1038/s41398-017-0015-4] [PMID: 29520063]
[46]
Cikankova, T.; Sigitova, E.; Zverova, M.; Fisar, Z.; Raboch, J.; Hroudova, J. Mitochondrial dysfunctions in bipolar disorder: effect of the disease and pharmacotherapy. CNS Neurol. Disord. Drug Targets, 2017, 16(2), 176-186.
[http://dx.doi.org/10.2174/1871527315666161213110518] [PMID: 27978794]
[47]
Adams, J.M.; Cory, S.; Adams, J.M. Cory SLife-or-death decisions by the Bcl-2 protein family. Trends Biochem Sci 26: 61-66. Trends Biochem. Sci., 2001, 26(1), 61-66.
[http://dx.doi.org/10.1016/S0968-0004(00)01740-0] [PMID: 11165519]
[48]
Guadagno, J.; Xu, X.; Karajgikar, M.; Brown, A.; Cregan, S.P. Microglia-derived TNFα induces apoptosis in neural precursor cells via transcriptional activation of the Bcl-2 family member Puma. Cell Death Dis., 2013, 4(3)e538
[http://dx.doi.org/10.1038/cddis.2013.59] [PMID: 23492769]
[49]
Arnett, M.G.; Ryals, J.M.; Wright, D.E. Pro-NGF, sortilin, and p75NTR: potential mediators of injury-induced apoptosis in the mouse dorsal root ganglion. Brain Res., 2007, 1183(1), 32-42.
[http://dx.doi.org/10.1016/j.brainres.2007.09.051] [PMID: 17964555]
[50]
Chen, L.W.; Yung, K.K.; Chan, Y.S.; Shum, D.K.; Bolam, J.P. The proNGF-p75NTR-sortilin signalling complex as new target for the therapeutic treatment of Parkinson’s disease. CNS Neurol. Disord. Drug Targets, 2008, 7(6), 512-523.
[http://dx.doi.org/10.2174/187152708787122923] [PMID: 19128208]
[51]
Sun, Y.; Lim, Y.; Li, F. ProBDNF collapses neurite outgrowth of primary neurons by activating RhoA. PLoS One, 2012, 7(4)e35883
[http://dx.doi.org/10.1371/journal.pone.0035883] [PMID: 22558255]
[52]
Wu, B.W.; Wu, M.S.; Guo, J.D. Effects of microRNA-10a on synapse remodeling in hippocampal neurons and neuronal cell proliferation and apoptosis through the BDNF-TrkB signaling pathway in a rat model of Alzheimer’s disease. J. Cell. Physiol., 2018, 233(7), 5281-5292.
[http://dx.doi.org/10.1002/jcp.26328] [PMID: 29215712]
[53]
Povarnina, PY; Garibova, TL; Gudasheva, TA; Seredenin, SB Antidepressant effect of an orally administered dipeptide mimetic of the brain-derived neurotrophic factor.Acta naturae, 2018, 10(3), 81-4.
[54]
Li, J.; Zhou, Y.; Du, G. Bioinformatic analysis reveals key genes and pathways in aging brain of senescence-accelerated mouse P8 (SAMP8). CNS Neurol. Disord. Drug Targets, 2018, 17(9), 712-22.
[http://dx.doi.org/10.2174/1871527316666170518170422] [PMID: 28524001]
[55]
Li, Q.; Wang, P.; Huang, C. N-acetyl serotonin protects neural progenitor cells against oxidative stress-induced apoptosis and improves neurogenesis in adult mouse hippocampus following traumatic brain injury. J. Mol. Neurosci., 2019, 67(4), 574-588.
[http://dx.doi.org/10.1007/s12031-019-01263-6] [PMID: 30684239]
[56]
Pang, P.T.; Lu, B. Regulation of late-phase LTP and long-term memory in normal and aging hippocampus: role of secreted proteins tPA and BDNF. Ageing Res. Rev., 2004, 3(4), 407-430.
[57]
Zhou, XF; Li, WP; Zhou, FH et al.Differential effects of endogenous brain-derived neurotrophic factor on the survival of axotomized sensory neurons in dorsal root ganglia: a possible role for the p75 neurotrophin receptor, 2005, 132(3), 591-603.
[http://dx.doi.org/10.1016/j.neuroscience.2004.12.034]
[58]
Balkowiec, A.; Katz, D.M. Cellular mechanisms regulating activity-dependent release of native brain-derived neurotrophic factor from hippocampal neurons. J. Neurosci., 2002, 22(23), 10399-407.
[59]
Goodman, LJ; Valverde, J; Lim, F Regulated release and polarized localization of brain-derived neurotrophic factor in hippocampal neurons. Mol Cell Neurosci , 7(3), 222-38.
[http://dx.doi.org/10.1006/mcne.1996.0017]
[60]
Jiang, X.; Tang P-C, ; Chen, Q. et al.Cordycepin exerts neuroprotective effects via an anti-apoptotic mechanism based on the mitochondrial pathway in rotenone-induced parkinsonism rat model. CNS Neurol. Disord. Drug Targets, 2019, 18(8), 609-20.
[http://dx.doi.org/10.2174/1871527318666190905152138]
[61]
Santos, L.C.; Vogel, R.; Chipuk, J.E.; Birtwistle, M.R.; Stolovitzky, G.; Meyer, P. Mitochondrial origins of fractional control in regulated cell death. Nat. Commun., 2019, 10(1), 1313.
[http://dx.doi.org/10.1038/s41467-019-09275-x]
[62]
Zhang, Y.; Sun, C.; Xiao, G.; Gu, Y. Host defense peptide Hymenochirin-1B induces lung cancer cell apoptosis and cell cycle arrest through the mitochondrial pathway. Biochem. Biophys. Res. Commun., 2019, 512(2), 269-75.
[http://dx.doi.org/10.1016/j.bbrc.2019.03.029] [PMID: 30885438]
[63]
Ghiasi, P.; Hosseinkhani, S.; Ansari, H. Reversible permeabilization of the mitochondrial membrane promotes human cardiomyocyte differentiation from embryonic stem cells. J. Cell. Physiol., 2018, 234(1), 521-536.
[64]
Yi, G.; Li, L.; Luo, M. Heat stress induces intestinal injury through lysosome- and mitochondria-dependent pathway in vivo and in vitro. Oncotarget, 2017, 8(25), 40741-40755.
[http://dx.doi.org/10.18632/oncotarget.16580] [PMID: 28380464]
[65]
Wang, S.; Ma, F.; Huang, L. Dl-3-n-Butylphthalide (NBP): a promising therapeutic agent for ischemic stroke. CNS Neurol. Disord. Drug Targets, 2018, 17(5), 338-347.
[http://dx.doi.org/10.2174/1871527317666180612125843] [PMID: 29895257]
[66]
Wang, L.; Zhao, T.; Wang, S.; Jin, J.; Cai, Y.; Wang, F. Expression, purification, and in vitro mitochondrial interaction analysis of full-length and truncated human tumor suppresser p53. Biosci. Biotechnol. Biochem., 2019, 83(7), 1220-6.
[http://dx.doi.org/10.1080/09168451.2019.1594674] [PMID: 30898040]