MAO-B Inhibitor, KDS2010, Alleviates Spinal Nerve Ligation-induced Neuropathic Pain in Rats Through Competitively Blocking the BDNF/TrkB/NR2B Signaling

Abstract

MAO-B inhibitors have been implicated to reverse neuropathic pain behaviors. Our previous study has demonstrated that KDS2010 (KDS), a newly developed reversible MAO-B inhibitor, could attenuate Paclitaxel (PTX)-induced tactile hypersensitivity in mice through suppressing reactive oxidant species (ROS)-decreased inhibitory GABA synaptic transmission in the spinal cord. In this study, we evaluated the analgesic effect of KDS under a new approach, in which KDS acts on dorsal horn sensory neurons to reduce excitatory transmission. Oral administration of KDS effectively enhanced mechanical thresholds in the spinal nerve ligation (SNL) induced neuropathic pain in rats. Moreover, we discovered that although treatment with KDS increased brain-derived neurotrophic factor (BDNF) levels, KDS inhibited Tropomyosin receptor kinase B (TrkB) receptor activation, suppressing increased p-NR2B-induced hyperexcitability in spinal dorsal horn sensory neurons after nerve injury. In addition, KDS showed its anti-inflammatory effects by reducing microgliosis and astrogliosis and the activation of MAPK and NF-kappa B inflammatory pathways in these glial cells. The levels of ROS production in the spinal cords after the SNL procedure were also decreased with KDS treatment. Taken together, our results suggest that KDS may represent a promising therapeutic option for treating neuropathic pain. Perspective: Our study provides evidence suggesting the mechanisms by which KDS, a novel MAO-B inhibitor, can be effective in pain relief. KDS, by targeting multiple mechanisms involved in BDNF/TrkB/NR2B-related excitatory transmission and neuroinflammation, may represent the next future of pain medicine. (C) 2022 The Author(s). Published by Elsevier Inc. on behalf of United States Association for the Study of Pain, Inc.