PD23-05 THERAPEUTIC EFFECTS OF KCC2 CHLORIDE ION TRANSPORTER ACTIVATION ON DETRUSOR OVERACTIVITY IN MICE WITH SPINAL CORD INJURY

Abstract

You have accessJournal of UrologyCME1 Apr 2023PD23-05 THERAPEUTIC EFFECTS OF KCC2 CHLORIDE ION TRANSPORTER ACTIVATION ON DETRUSOR OVERACTIVITY IN MICE WITH SPINAL CORD INJURY Kyohei Watanabe, Masaru Ishibashi, Takahisa Suzuki, Atsushi Otsuka, Naoki Yoshimura, Hideaki Miyake, and Atsuo Fukuda Kyohei WatanabeKyohei Watanabe More articles by this author , Masaru IshibashiMasaru Ishibashi More articles by this author , Takahisa SuzukiTakahisa Suzuki More articles by this author , Atsushi OtsukaAtsushi Otsuka More articles by this author , Naoki YoshimuraNaoki Yoshimura More articles by this author , Hideaki MiyakeHideaki Miyake More articles by this author , and Atsuo FukudaAtsuo Fukuda More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003296.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: GABA generally exerts inhibitory effects in the central nervous system, including the spinal cord. However, it may also act as an excitatory transmitter under pathological conditions, such as injury. This paradoxical signaling of GABA is dependent on the intracellular Cl- concentration in neurons. K+-Cl-co-transporter 2 (KCC2) maintains a low intracellular Cl- concentration by pumping K+ and Cl- ions out of the cell. We aimed to clarify whether the down regulation of KCC2 in the sacral parasympathetic nucleus (SPN) of the lumbosacral spinal cord, from which the efferent pathway innervating the bladder originates, causes cellular hyperexcitability and triggers detrusor overactivity (DO) in spinal cord injury (SCI). METHODS: SCI was produced by the Th8-9 spinal cord transection in female C57BL/6 mice. We randomly divided mice into four groups: a spinal cord intact (SI)-vehicle, SI-CLP290, SCI-vehicle, and SCI-CLP290 groups. At 4 weeks after SCI, CLP290, a KCC2 activator was administered, and cystometry was performed. Thereafter, neuronal activity with c-fos staining and KCC expression in the cholinergic preganglionic parasympathetic neurons in the SPN were examined using immunohistochemistry. Firing properties of neurons in the SPN region were evaluated by extracellular recordings in spinal cord slice preparations. RESULTS: DO evident as non-voiding contractions (NVC) was significantly reduced by CLP290 treatment in SCI mice (Figure 1A-D). The number of c-fos-positive cells and co-expression of c-fos in choline acetyltransferase (ChAT)-positive cells were decreased in the SPN region of SCI-CLP290 group vs. SCI-vehicle group. KCC2 immunoreactivity was present on the cell membrane of SPN neurons, and the normalized fluorescence intensity of KCC2 in ChAT-positive SPN neurons was decreased in SCI-vehicle group, vs. SI-vehicle group, but recovered in SCI-CLP290 group. Extracellular recordings showed that CLP290 suppressed the high frequency firing activity of SPN neurons in SCI mice (Figure 1E-F). CONCLUSIONS: This study is the first report to suggest that activation of KCC2 chloride ion transporter may be a therapeutic modality for the treatment of SCI-induced DO by targeting bladder efferent pathways. Source of Funding: This work supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science and a HUSM Grant-in-Aid © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e672 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kyohei Watanabe More articles by this author Masaru Ishibashi More articles by this author Takahisa Suzuki More articles by this author Atsushi Otsuka More articles by this author Naoki Yoshimura More articles by this author Hideaki Miyake More articles by this author Atsuo Fukuda More articles by this author Expand All Advertisement PDF downloadLoading ...