title: Inhibition of CaMKIV relieves streptozotocin-induced diabetic neuropathic pain through regulation of HMGB1.
abstract: The pathogenesis of diabetic neuropathic pain is complicated and its underlying mechanisms remain unclear. Calmodulin-dependent protein kinases (CaMKs) IV (CaMKIV), one of CaMKs, regulates several transcription factors in pain mechanisms. High-mobility group box 1 (HMGB1) is a key mediator in diabetic neuropathic pain. This study aims to find the roles and mechanisms of CaMIV in diabetic neuropathic pain.
  
  
  
  Diabetic animal models were constructed by injecting with streptozotocin (STZ) intraperitoneally. They were randomly divided into seven groups (n = 6 per group): Naive, Normal Saline, STZ, STZ + Sham, STZ + DMSO and STZ + KN93 (an inhibitor of CaMKIV) (50 μg), STZ + KN93 (100 μg), which received KN93 (50 or 100 μg) intrathecally after the administration of STZ. Phospho-CaMKIV (pCaMKIV) and HMGB1 expression in rat dorsal root ganglion (DRG) and RAW264.7 cell line were measured by western blot. Distribution of pCaMKIV immune reactivity in different subpopulations of DRG neurons was measured by double-immunofluorescence staining.
  
  
  
  The pCaMKIV and HMGB1 in DRG significantly increased after STZ administration, and pCaMKIV can regulate the expression of HMGB1 based on both cellular and animal models. Pretreatment with CaMKIV inhibitor attenuated STZ-induced mechanical allodynia and thermal hyperalgesia, as well as reduced HMGB1 expression in the DRG.
  
  
  
  This study demonstrates that CaMKIV can relieve STZ-induced diabetic neuropathic pain. The mechanism of this function depended on the process: pCaMKIV localized in the nuclei of DRG neurons and regulated HMGB1 which was an important mediator of neuropathic pain. These findings reported CaMKIV may be a potential target or important node in relieving diabetic neuropathic pain.
authors.affiliation: Department of Anesthesiology, Peking Union Medical College Hospital, CAMS&PUMC, No.1, Wangfujing, DongCheng District, Beijing, 100730, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology, Peking Union Medical College Hospital, CAMS&PUMC, No.1, Wangfujing, DongCheng District, Beijing, 100730, China.
authors.forename: Le
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Anesthesiology, Peking Union Medical College Hospital, CAMS&PUMC, No.1, Wangfujing, DongCheng District, Beijing, 100730, China.
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, Peking Union Medical College Hospital, CAMS&PUMC, No.1, Wangfujing, DongCheng District, Beijing, 100730, China.
authors.forename: Zhiyao
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Institute of Basic Medical Sciences Chinese Academy of Medical Science, Neuroscience Center, School of Basic Medicine Peking Union Medical College, Department of Anatomy, Histology and Embryology, 100005, Beijing, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Anesthesiology, Peking Union Medical College Hospital, CAMS&PUMC, No.1, Wangfujing, DongCheng District, Beijing, 100730, China. garybeijing@163.com.
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000378:metabolism; D024243:HMGB1 Protein / Q000096:biosynthesis / Q000502:physiology*; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D009474:Neurons / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects; D010766:Phosphorylation; D051381:Rats; D013311:Streptozocin; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D024243:HMGB1 Protein; D013311:Streptozocin; D013449:Sulfonamides; C104200:Hbp1 protein, rat; C072105:KN 93; D000096926:Benzenesulfonamides; C517686:Camk4 protein, rat
keywords: CaMKIV; Diabetic neuropathic pain; Dorsal root ganglion; HMGB1; Neuron