Synergistic amelioration of glaucoma by exogenous BDNF supplementation and microRNA-93 inhibitors via regulating Rho/ROCK and BDNF/TrkB/CREB signaling pathways

Kaiming Li; Bo Long; Wei Chen; Min Gan; Manhua Xu

doi:10.1007/s00210-025-03817-5

Synergistic amelioration of glaucoma by exogenous BDNF supplementation and microRNA-93 inhibitors via regulating Rho/ROCK and BDNF/TrkB/CREB signaling pathways

Naunyn Schmiedebergs Arch Pharmacol. 2025 Jun 26. doi: 10.1007/s00210-025-03817-5. Online ahead of print.

Authors

Kaiming Li¹, Bo Long², Wei Chen², Min Gan², Manhua Xu³

Affiliations

¹ Ophthalmology Department, Suining Central Hospital, No. 127 Desheng West Road Chuanshan District, Suining City, 629000, Sichuan Province, China. likm0656@hotmail.com.
² Ophthalmology Department, Suining Central Hospital, No. 127 Desheng West Road Chuanshan District, Suining City, 629000, Sichuan Province, China.
³ Ophthalmology Department, Suining Central Hospital, No. 127 Desheng West Road Chuanshan District, Suining City, 629000, Sichuan Province, China. 28767696@qq.com.

PMID: 40569368
DOI: 10.1007/s00210-025-03817-5

Abstract

Current study aims to investigate the ameliorative effects of exogenous brain-derived neurotrophic factor (BDNF) supplementation, in combination with microRNA-93 (miR-93) inhibitors, on acute glaucoma mouse models, and to delve into the underlying mechanisms. Oxygen-glucose deprivation/reperfusion (OGD/R)-induced retinal ganglion cells (RGCs) apoptosis was assessed using the MTT assay and flow cytometry. Acute glaucoma was induced by elevating intraocular pressure (IOP) in mice, which were divided into groups receiving PBS, miR-93 inhibitors, BDNF, or combination therapy, alongside a healthy control group. Retinal tissues were analyzed for thickness, ganglion cell layer (GCL) cell counts, and pathological changes. Real-time quantitative PCR (qPCR) and Western blotting assessed mRNA and protein expression related to the Rho/ROCK and BDNF/TrkB/CREB signaling pathways. Rescue experiments employing specific inhibitors and agonists targeting these pathways were conducted to further elucidate the mechanisms involved. The combination therapy demonstrated a significant improvement in the survival of RGCs by inhibiting apoptosis induced by OGD/R. Additionally, this combined treatment ameliorated the elevation of IOP, retinal damage, and reduction in retinal thickness observed in glaucoma models. Notably, the combination therapy resulted in increased ganglion cell layer (GCL) cell counts compared to monotherapy groups, indicating a synergistic effect on retinal preservation (all P < 0.05). Western blot revealed that combination therapy inhibited the Rho/ROCK pathway and ECM-related protein expression, while enhancing BDNF/TrkB/CREB signaling and MMP-related protein expression (all P < 0.05). Rescue experiments showed that BDNF inhibitors and Rho agonists reversed these effects. In conclusion, the combination of BDNF supplementation and miR-93 inhibitors exerts synergistic effects in acute glaucoma by inhibiting the Rho/ROCK pathway and activating the BDNF/TrkB/CREB signaling pathway.

Keywords: BDNF/TrkB signaling pathway; Brain-derived neurotrophic factor; Glaucoma; MicroRNA-93 inhibitor; Retinal damage; Retinal ganglion cell; Rho/ROCK signaling pathway.