Theranostics 2019; 9(6):1651-1665. doi:10.7150/thno.29703
A Novel Peptide Interfering with proBDNF-Sortilin Interaction Alleviates Chronic Inflammatory Pain
1. Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
2. School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
3. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
4. State Key Laboratory of Digestive Diseases, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
5. LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
6. CUHK Shenzhen Research Institute, Shenzhen, China.
*These authors contributed equally: I Ho, X Liu, Y Zou
Ho IHT, Liu X, Zou Y, Liu T, Hu W, Chan H, Tian Y, Zhang Y, Li Q, Kou S, Chan CS, Gin T, Cheng CHK, Wong SH, Yu J, Zhang L, Wu WKK, Chan MTV. A Novel Peptide Interfering with proBDNF-Sortilin Interaction Alleviates Chronic Inflammatory Pain. Theranostics 2019; 9(6):1651-1665. doi:10.7150/thno.29703. Available from http://www.thno.org/v09p1651.htm
Rationale: Brain-derived neurotrophic factor (BDNF) is a key mediator in the development of chronic pain. Sortilin is known to interact with proBDNF and regulate its activity-dependent secretion in cortical neurons. In a rat model of inflammatory pain with intraplantar injection of complete Freund's adjuvant (CFA), we examined the functional role of proBDNF-sortilin interaction in dorsal root ganglia (DRG).
Methods: Expression and co-localization of BDNF and sortilin were determined by immunofluorescence. ProBDNF-sortilin interaction interface was mapped using co-immunoprecipitation and bimolecular fluorescence complementation assay. The analgesic effect of intrathecal injection of a synthetic peptide interfering with proBDNF-sortilin interaction was measured in the CFA model.
Results: BDNF and sortilin were co-localized and their expression was significantly increased in ipsilateral L4/5 DRG upon hind paw CFA injection. In vivo adeno-associated virus-mediated knockdown of sortilin-1 in L5 DRG alleviated pain-like responses. Mapping by serial deletions in the BDNF prodomain indicated that amino acid residues 71-100 supported the proBDNF-sortilin interaction. A synthetic peptide identical to amino acid residues 89-98 of proBDNF, as compared with scrambled peptide, was found to interfere with proBDNF-sortilin interaction, inhibit activity-dependent release of BDNF in vitro and reduce CFA-induced mechanical allodynia and heat hyperalgesia in vivo. The synthetic peptide also interfered with capsaicin-induced phosphorylation of extracellular signal-regulated kinases in ipsilateral spinal cord of CFA-injected rats.
Conclusions: Sortilin-mediated secretion of BDNF from DRG neurons contributes to CFA-induced inflammatory pain. Interfering with proBDNF-sortilin interaction reduced activity-dependent release of BDNF and might serve as a therapeutic approach for chronic inflammatory pain.
Keywords: analgesics, peptide drug, neurotransmitter, cell-penetrating peptide, protein transduction domain, Tat