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OPEN
received: 22 December 2015 accepted: 13 May 2016 Published: 02 June 2016
Peripheral Brain Derived Neurotrophic Factor Precursor Regulates Pain as an Inflammatory Mediator Cong Luo1,*, Xiao-Lin Zhong2,*, Fiona H. Zhou3,*, Jia-yi Li3, Pei Zhou1, Jun-Mei Xu1, Bo Song4, Chang-Qi Li2, Xin-Fu Zhou3 & Ru-Ping Dai1 The precursor of brain derived neurotrophic factor (proBDNF), the unprocessed BDNF gene product, binds to its receptors and exerts the opposing biologic functions of mature BDNF. proBDNF is expressed in the peripheral tissues but the functions of peripheral proBDNF remain elusive. Here we showed that proBDNF and its predominant receptor, p75 pan-neurotrophin receptor were upregulated in the nerve fibers and inflammatory cells in the local tissue in inflammatory pain. Neutralization of proBDNF by polyclonal antibody attenuated pain in different models of inflammatory pain. Unilateral intraplantar supplementation of proBDNF by injecting exogenous proBDNF or ectopic overexpression resulted in pain hypersensitivity and induced spinal phosphorylated extracellular signal-regulated kinase activation. Exogenous proBDNF injection induced the infiltration of inflammatory cells and the activation of proinflammatory cytokines, suggesting that inflammatory reaction contributed to the pro-algesic effect of proBDNF. Finally, we generated monoclonal anti-proBDNF antibody that could biologically block proBDNF. Administration of monoclonal Ab-proBDNF attenuated various types of inflammatory pain and surgical pain. Thus, peripheral proBDNF is a potential pain mediator and antiproBDNF pretreatment may alleviate the development of inflammatory pain. Brain derived neurotrophic factor (BDNF) is a neurotrophin playing multiple biologic roles including neuronal survival, shaping neurons and synaptic plasticity1. Like other neurotrophins, BDNF is initially synthesized as a precursor, which is then cleaved by proteases to mature BDNF (mBDNF)2–4. The prodomain of BDNF is essential for the correcting folding and secretory pathway of mBDNF. Not only as an intermediate during the synthesis of mBDNF, proBDNF also binds to its receptors, p75 pan-neurotrophin receptor (p75NTR) and sortilin, and mainly exerts opposing biologic effects of mBDNF in the central nervous system. For example, in contrast to mBDNF, proBDNF can play an active role in neuronal apoptosis, axon pruning and negatively regulates hippocampal dendritic complexity and spine density5,6. In addition to the abundant expression in the central nervous system, proBDNF is also expressed in the peripheral nervous system and other tissues such as skin, olfactory epithelium and intestine7. In the skin, proBDNF immunoreactivity was observed in the keratinocytes and nerve fibers; and in the intestine, proBDNF was located in the myenteric plexus layer and in the mucosal and submucosal layers7. Despite the extensive studies about the role of proBDNF in the central nervous system, the biologic roles of proBDNF in the peripheral tissues still remain elusive. Here, we reported that proBDNF in the peripheral tissues is an inflammatory mediator regulating the inflammatory pain. Anti-proBDNF antibody could attenuate various types of inflammatory pain and may be a potential candidate to ameliorate the inflammatory pain.
1
Department of Anesthesiology, The Second Xiang-Ya Hospital of Central South University, Changsha 410000, Hunan, China. 2Department of Anatomy and Neurobiology, School of Basic Medical of Science, Central South University, Changsha 410000, Hunan, China. 3School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, SA 5000, Australia. 4Shanghai Yile Biotechnology Co., Ltd. 466 Yindu Road, Shanghai 200231, P.R.China. *These authors contributed equally to this work. Correspondence and requests for materials should be addressed to R.-P.D. (email:
[email protected]) Scientific Reports | 6:27171 | DOI: 10.1038/srep27171
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Figure 1. Upregulation of proBDNF in the local tissue in acute and persistent inflammatory pain in mice. (A) Representative Western blot (a) and their semi-quantitative analyses of mature BDNF (b), proBDNF (c) and their ratio (d) in the local tissue after 10 μL 5% formalin intra-plantar injection into Kunming mice (*p
