FK962 protects retinal ganglion cell under hypoxia/reoxygenation: Possible involvement of glial cell line-derived neurotrophic factor signaling pathway.

Autor: Kobayashi-Otsugu M; Senju Pharmaceutical Co., Ltd, 6-4-3, Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan., Kishimoto Y; Senju Pharmaceutical Co., Ltd, 6-4-3, Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan., Azuma M; Senju Pharmaceutical Co., Ltd, 6-4-3, Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan., Fukiage C; Senju Pharmaceutical Co., Ltd, 6-4-3, Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan. Electronic address: chiho-fukiage@senju.co.jp.
Jazyk: angličtina
Zdroj: Experimental eye research [Exp Eye Res] 2024 Nov; Vol. 248, pp. 110099. Date of Electronic Publication: 2024 Sep 14.
DOI: 10.1016/j.exer.2024.110099
Abstrakt: Loss of retinal ganglion cells (RGCs) is the cause of visual impairment and blindness in glaucoma. Previously, our studies showed that FK962 (N-[1-acetylpiperidin-4-yl]-4-fluorobenzamide) promoted neurite elongation in rat RGCs and trigeminal ganglion (TG) cells. In TG cells, glial cell line-derived neurotrophic factor (GDNF) is known to be involved in the mechanism. The purpose of the present study is to investigate whether, 1) FK962 shows an RGC-protective effect under hypoxia/reoxygenation (H/R) and 2) GDNF is involved in the neuroprotective mechanism of FK962. Rat primary retinal cells were cultured under 24-h hypoxia/24-h reoxygenation conditions, with or without FK962, recombinant GDNF, GDNF antibody and RET receptor tyrosine kinase inhibitor, GSK3179106. Cells were co-immunostained with RBPMS and Neurofilament 200 as a RGC marker, and the number of survived RGCs was counted. Results showed H/R treatment decreased the number of survived RGCs. FK962 promoted RGC survival under H/R by a bell-shaped dose response, with the highest RGC-protective effect of 10 -8  M. The protective effect was the same level with 10 -12  M exogenous GDNF. Addition of GDNF antibody or GSK3179106 counteracted the neuroprotective effect of FK962. From these results, it is suggested that FK962 ameliorates RGC death under H/R, possibly via a GDNF signaling pathway.
(Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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