A Novel Peptide Interfering with proBDNF-Sortilin Interaction Alleviates Chronic Inflammatory Pain

• Published in: Theranostics 2019-01, Vol.9 (6), p.1651-1665
• Main Authors: Ho, Idy H T, Liu, Xiaodong, Zou, Yidan, Liu, Taian, Hu, Wei, Chan, Hung, Tian, Yuanyuan, Zhang, Yuchen, Li, Qing, Kou, Shanglong, Chan, Chee Sam, Gin, Tony, Cheng, Christopher H K, Wong, Sunny H, Yu, Jun, Zhang, Lin, Wu, William K K, Chan, Matthew T V
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Vesicular Transport - antagonists & inhibitors; Analgesics - administration & dosage; Analgesics - pharmacology; Animals; Brain-Derived Neurotrophic Factor - antagonists & inhibitors; Chronic Pain - drug therapy; Disease Models, Animal; Ganglia, Spinal - drug effects; Gene Knockdown Techniques; Inflammation - complications; Peptides - administration & dosage; Peptides - pharmacology; Rats; Research Paper; Treatment Outcome
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.29703

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). 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. BDNF and sortilin were co-localized and their expression was significantly increased in ipsilateral L4/5 DRG upon hind paw CFA injection. 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 and reduce CFA-induced mechanical allodynia and heat hyperalgesia . The synthetic peptide also interfered with capsaicin-induced phosphorylation of extracellular signal-regulated kinases in ipsilateral spinal cord of CFA-injected rats. 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.