Antiallodynic effects of KDS2010, a novel MAO-B inhibitor, via ROS-GABA inhibitory transmission in a paclitaxel-induced tactile hypersensitivity model

Abstract

Monoamine oxidase (MAO) inhibitors have been investigated for the treatment of neuropathic pain. Here, we assessed the antiallodynic effects of a novel MAO-B inhibitor, KDS2010, on paclitaxel (PTX)-induced mechanical hypersensitivity. Oral administration of KDS2010 effectively relieved PTX-induced mechanical hypersensitivity in a dose-dependent manner. KDS2010 (25 mg/Kg) significantly prevented and suppressed PTX-induced pain responses with minimal effects on the body weight, motor activity, and working memory. KDS2010 significantly reduced reactive astrocytosis and reactive oxygen species (ROS) level in the L4–L6 spinal cord of PTX-treated mice. Furthermore, KDS2010 reversed the attenuation of GABAergic spontaneous inhibitory postsynaptic current (sIPSC) frequency in spinal dorsal horn neurons, although it failed to restore the reduced tonic GABAA inhibition nor the increased GABA transporter 1 (GAT1) expression in PTX-treated mice. In addition, bath application of a reactive oxygen species (ROS) scavenger (PBN) restored the sIPSC frequency in PTX-treated mice but not in control and PTX + KDS2010-treated mice. These results indicated that the antiallodynic effect of KDS2010 is not due to a MAO-B-dependent GABA production. Finally, PBN alone also exerted a similar analgesic effect as KDS2010, but a co-treatment of PBN with KDS2010 showed no additive effect, suggesting that inhibition of MAO-B-dependent ROS production is responsible for the analgesic effect by KDS2010 on PTX-induced allodynia. Overall, KDS2010 attenuated PTX-induced pain behaviors by restoring the altered ROS level and GABAergic inhibitory signaling in the spinal cord, suggesting that KDS2010 is a promising therapeutic strategy for chemotherapy-induced peripheral neuropathy.

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

“…Notably, the involvement of oxidative stress has been regarded as an important mechanism in the pathogenesis of neuropathic pain 48,51 . In a line with this, our recent study has shown increased ROS levels contribute to decreased spinal GABA inhibition in a PTX-induced pain hypersensitivity mouse model 46 . KDS, as an MAO-B inhibitor, alleviated pain behaviors by suppressing ROS generation-decreased GABA release, theoretically from spinal astrocytes.…”

“…1B). Based on the previous studies which investigated the pharmacokinetics and toxicokinetics of orally administered KDS 23 , and our primary data on the analgesic effect of KDS on pain models 46 , the dose of 25mg/kg was selected for the treatment due to its effectiveness and limited side effects on the body weight and other essential brain functions (the rats in the KDS-treated group had similar growth in weight, compared to the rats in the SNL-untreated groups). The first round of treatment was conducted from POD3 to POD9.…”

“…Moreover, the administration of TrkB phosphorylation inhibitor in the spinal cord has been demonstrated to be able to prevent the initiation and development of nerve injury-induced pain hypersensitivity in mice 55 . In the previous work, we have shown that KDS, an MAO-B inhibitor, exhibited its anti-allodynic effect in chemotherapyinduced peripheral neuropathy (CIPN) in mice 46 . This agrees with the early study which revealed Selegiline, a selective MAO-B inhibitor, could reverse partial sciatic nerve ligation-induced mechanical allodynia 53 .…”

Protein Arginine Methyltransferase 5 Contributes to Paclitaxel-Induced Neuropathic Pain by Activating Transient Receptor Potential Vanilloid 1 Epigenetic Modification in Dorsal Root Ganglion

“…Inflammation- and ROS-associated pathways have been identified as key players in the PTX-induced neuropathic pain. 19,37 Based on the above-mentioned evidence, our study investigated the role of NOX4 in PRMT5-associated PTX-induced neuropathic pain. Moreover, GLX is a reported NOX4 inhibitor by reducing ROS production.…”

Macrophages and glial cells: Innate immune drivers of inflammatory arthritic pain perception from peripheral joints to the central nervous system

“…Conversely, inhibition of MAO-B decreased hippocampal astrocytic GABA in CIA, rescued cognitive impairment, and alleviated joint swelling in CIA mice ( 183 ). This same group has shown that inhibiting MAO-B has an analgesic effect reversing mechanical allodynia present in neuropathic pain ( 184 ).…”