Case Center for Biomolecular Engineering, Department of Biomedical Engineering, School of Engineering, Case Western Reserve University, Cleveland, Ohio, USA.
Department of Pharmacology, Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
FASEB J. 2018 Jun;32(6):3289-3300. doi: 10.1096/fj.201701250R. Epub 2018 Jan 24.
No clinically approved therapies are currently available that prevent the onset of photoreceptor death in retinal degeneration. Signaling between retinal neurons is regulated by the release and uptake of neurotransmitters, wherein GABA is the main inhibitory neurotransmitter. In this work, novel 3-chloropropiophenone derivatives and the clinical anticonvulsants tiagabine and vigabatrin were tested to modulate GABA signaling and protect against light-induced retinal degeneration. Abca4Rdh8 mice, an accelerated model of retinal degeneration, were exposed to intense light after prophylactic injections of one of these compounds. Imaging and functional assessments of the retina indicated that these compounds successfully protected photoreceptor cells from degeneration to maintain a full-visual-field response. Furthermore, these compounds demonstrated a strong safety profile in wild-type mice and did not compromise visual function or damage the retina, despite repeated administration. These results indicate that modulating inhibitory GABA signaling can offer prophylactic protection against light-induced retinal degeneration.-Schur, R. M., Gao, S., Yu, G., Chen, Y., Maeda, A., Palczewski, K., Lu, Z.-R. New GABA modulators protect photoreceptor cells from light-induced degeneration in mouse models.
目前尚无临床批准的疗法可预防视网膜变性中光感受器细胞的死亡。视网膜神经元之间的信号传递受神经递质的释放和摄取调节，其中 GABA 是主要的抑制性神经递质。在这项工作中，新型 3-氯丙酰苯酮衍生物以及临床抗惊厥药噻加宾和氨己烯酸被测试用于调节 GABA 信号传递并预防光诱导的视网膜变性。Abca4Rdh8 小鼠是视网膜变性的加速模型，在预防性注射这些化合物之一后，暴露于强光下。对视网膜的成像和功能评估表明，这些化合物成功地保护光感受器细胞免受变性，以维持全视野反应。此外，这些化合物在野生型小鼠中表现出很强的安全性，并且尽管重复给药，也不会损害视觉功能或损伤视网膜。这些结果表明，调节抑制性 GABA 信号传递可以提供针对光诱导的视网膜变性的预防性保护。-Schur，R. M.，Gao，S.，Yu，G.，Chen，Y.，Maeda，A.，Palczewski，K.，Lu，Z.-R. 新型 GABA 调节剂可保护光感受器细胞免受小鼠模型中光诱导的变性。
