| 摘要: | 青光眼屬於神經退化性疾病，其特徵是漸進式視野喪失和視網膜神經節細胞 (retinal ganglion cell, RGC) 病變，一般治療通常是以調節眼內壓 (intraocular pressure, IOP) 為主。然而，由於詳細的致病機制仍未確實了解，部分青光眼患者在眼壓控制下仍持續惡化。近年來，出現了越來越多研究結果指出神經發炎可能為潛在的青光眼治療標的。本研究利用體外和體內青光眼模型研究新型 HDAC8 抑制劑 – H7E 的保護作用。H7E 在電腦模擬與和細胞實驗均表現出針對 HDAC8 的選擇性。在視網膜穆勒膠細胞 (M?ller glial cell line, rMC-1) 實驗中，H7E 透過抑制胞外 MMP-9 活性和 MCP-1 水平來減少發炎反應，這可能與抑制 MAPK 磷酸化有關，特別是 ERK 和 JNK。此外，H7E 透過抑制 caspase-3 的裂解，防止氧化壓力引起之視網膜前體細胞 (retinal precursor cell line, R28) 凋亡。在 NMDA 誘導的視網膜病變之小鼠動物模式中，經視網膜電位圖 (ERG) 評估和光學相干斷層掃描 (OCT)，H7E 有效改善視網膜功能性和結構性缺陷。並且在視網膜針對 S100B、RBPMS 和 GFAP 蛋白的免疫染色結果也支持這些發現，顯示H7E腹腔注射給藥能顯著預防 NMDA 誘導的視網膜損傷。綜上所述，這些結果表明 H7E 透過專一性抑制 HDAC8 活性，以抑制 M?ller 膠質細胞活化和防止氧化壓力誘導視網膜發生凋亡來防止青光眼之視網膜損傷。
Glaucoma, a neurodegenerative disease characterized by gradual visual deterioration and the degeneration of retinal ganglion cells (RGCs), is typically managed by controlling intraocular pressure (IOP). However, some patients do not respond adequately due to unclear pathogenic mechanisms. Emerging evidence suggests neuroinflammation as a promising target for new antiglaucoma therapies. This study aimed to evaluate the protective effects of H7E, a novel HDAC8 inhibitor, in the context of glaucoma by employing both in vitro cell-based assays and in vivo animal models. H7E demonstrated selectivity against HDAC8 in silico and in vitro. In a M?ller glial cell line (rMC-1), H7E reduced inflammatory responses by inhibiting gelatinolytic activity of MMP-9 activity and reducing MCP-1 production in the supernatant, likely through inhibition of MAPK phosphorylation, particularly ERK and JNK. Additionally, H7E prevented apoptosis of retinal precursor cells (R28) from oxidative stress by inhibiting the cleavage of caspase-3. In the NMDA-induced retinal degeneration model in mice, H7E successfully mitigated both the functional and structural defects observed in the retina, as evidenced by electroretinography (ERG) and optical coherence tomography (OCT). Immunostaining of S100B, RBPMS, and GFAP in the retina supported these findings, showing that intraperitoneal administration of H7E markedly prevented NMDA-induced retinal damage. Overall, these results indicate that H7E provides a protective effect against glaucomatous retinal damage through its specific action on HDAC8, thus inhibiting M?ller glial activation, and preventing oxidative stress-induced retinal cell death. |
