Post-Transcriptional Regulation of Soluble Guanylate Cyclase that Governs Neuropathic Pain in Alzheimer's Disease.

Abstract

Many patients with Alzheimer's disease suffer from severe neuropathic pain. Soluble guanylate cyclase (sGC) is a critical enzyme of the nitric oxide (NO) signaling pathway. Binding of NO to a group of prosthetic heme on sGC initiates the second messenger cGMP synthesis, resulting in increases in the mechanical threshold for neuropathic pain. Nevertheless, the regulation of sGC remains unclear. Here, we aimed to figure out a strategy to reduce sGC levels by microRNA (miRNA) intervention. Bioinformatical studies were then performed to predict sGC-targeting miRNAs; additionally, an assay of dual luciferase reporter was used for evaluating the functional binding of miRNAs to sGC. Among all sGC-targeting miRNAs, in particularly we found that miR-142-5p markedly inhibited sGC protein translation by pairing to the 3'-UTR of the sGC mRNA. Orthotopic injection of adeno-associated virus carrying miR-142-5p significantly decreased sGC and sGMP levels, resulting in reduction of the neuropathic pain in rats with the left hind leg sciatic nerve injured in the tibia and peroneal branches. In summary, these data show that miR-142-5p induction in injured neurons may be an effective treatment for neuropathic pain and worthy of further investigation as a treatment for those patients with Alzheimer's disease and neuropathic pain.