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.

New Insights onNOXEnzymes in the Central Nervous System

“…Animal models of neuropathic pain consist of evaluating pain sensitization after peripheral injury. A number of studies suggested a role of NOX-derived ROS in this process of nociceptive hypersensitization (39,80), but two studies addressed this question using genetically modified mice.…”

Practical Considerations of Convection Enhanced Delivery for Novel Therapies Treating Spinal Cord Injury Related Neuropathic Pain

“…Neuropathic pain decreased with miR23b infusion that occurs as result of the NOX4 gene inactivated, where MiR23b protects GABAergic neurons against ROS/p38/c-JNK apoptotic cell death [61].A mouse model that utilized NOX4 and miR23b revealed both negative and positive impacts on neuropathic pain. Continually, Spinal nerve ligation (SNL) alters expression levels of miR-96, miR-182, and miR-183, suggesting that these molecules related to chronic neuropathic pain through translational regulation of painrelevant genes [62].…”

MicroRNA Biology and Pain

“…[89][90][91][92][93] Some have successfully provided the proof-of concept for a role of specific miRNAs in influencing behavior using rodent models 79,94-96 (Fig. 4).…”