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-ᴋB 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.