title: Molecular targeting of NOX4 for neuropathic pain after traumatic injury of the spinal cord.
abstract: Neuropathic pain is a well-known type of chronic pain caused by damage to the nervous system. Until recently, many researchers have primarily focused on identifying cellular or chemical sources of neuropathic pain or have approached neuropathic pain via the basis of biological study. We investigated whether both mmu-mir-23b (miR23b) and NADPH oxidase 4 (NOX4) antibody infusion can alleviate neuropathic pain by compensating for abnormally downregulated miR23b via reducing the expression of its target gene, NOX4, a reactive oxygen species (ROS) family member overexpressed in neuropathic pain. Ectopic miR23b expression effectively downregulated NOX4 and finally normalized glutamic acid decarboxylase 65/67 expression. Moreover, animals with neuropathic pain showed significantly improved paw withdrawal thresholds (PWTs) following miR23b infusion. Normalizing miR23b expression in tissue lesions, caused by neuropathic pain induction, reduced inflammatory mediators and increased several ROS scavengers. Moreover, γ-aminobutyric acid (GABA)ergic neurons coexpressed suboptimal levels of miR23b and elevated NOX4/ROS after pain induction at the cellular level. MiR23b finally protects GABAergic neurons against ROS/p38/c-Jun N-terminal kinase (JNK)-mediated apoptotic death. By evaluating the functional behavior of mice receiving pain/miR23b, normal/anti-miR23b, anti-miR23b/si-NOX4, pain/NOX4 antibody, pain/ascorbic acid, and pain/ascorbic acid/NOX4 antibody, the positive role of miR23b and the negative role of NOX4 in neuropathic pain were confirmed. Based on this study, we conclude that miR23b has a crucial role in the amelioration of neuropathic pain in injured spinal cord by inactivating its target gene, NOX4, and protection of GABAergic neurons from cell death. We finally suggest that infusion of miR23b and NOX4 antibody may provide attractive diagnostic and therapeutic resources for effective pain modulation in neuropathic pain.
authors.affiliation: Laboratory of Stem Cell Biology, Department of Biotechnology, College of Veterinary Medicine, Seoul National University, Seoul, Korea.
authors.forename: Y B
authors.initials: YB
authors.lastname: Im
authors.forename: M K
authors.initials: MK
authors.lastname: Jee
authors.forename: J I
authors.initials: JI
authors.lastname: Choi
authors.forename: H T
authors.initials: HT
authors.lastname: Cho
authors.forename: O H
authors.initials: OH
authors.lastname: Kwon
authors.forename: S K
authors.initials: SK
authors.lastname: Kang
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D058990:Molecular Targeted Therapy; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D009437:Neuralgia / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D009474:Neurons / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D035683:MicroRNAs; C534062:Mirn23b microRNA, mouse; D017382:Reactive Oxygen Species; D005680:gamma-Aminobutyric Acid; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse