Journal Article

Neuroprotective Effect of 4-Phenylbutyric Acid against Photo-Stress in the Retina

Nagai, Norihiro, Guzmán Mendoza, Naymel Alejandra, Ozawa, Yoko, Homma, Kohei, Negishi, Kazuno, Ban, Norimitsu, Osada, Hideto, Toda, Eriko, Tsubota, Kazuo

2021

Overview

Exposure to excessive visible light causes retinal degeneration and may influence the progression of retinal blinding diseases. However, there are currently no applied treatments. Here, we focused on endoplasmic reticulum (ER) stress, which can cause cellular degeneration and apoptosis in response to stress. We analyzed functional, histological, and molecular changes in the light-exposed retina and the effects of administering an ER-stress inhibitor, 4-phenylbutyric acid (4-PBA), in mice. We found that light-induced visual function impairment related to photoreceptor cell loss and outer segment degeneration were substantially suppressed by 4-PBA administration, following attenuated photoreceptor apoptosis. Induction of retinal ER stress soon after light exposure, represented by upregulation of the immunoglobulin heavy chain binding protein (BiP) and C/EBP-Homologous Protein (CHOP), were suppressed by 4-PBA. Concurrently, light-induced oxidative stress markers, Nuclear factor erythroid 2–related factor 2 (Nrf2) and Heme Oxygenase 1 (HO-1), and mitochondrial apoptotic markers, B-cell lymphoma 2 apoptosis regulator (Bcl-2)-associated death promoter (Bad), and Bcl-2-associated X protein (Bax), were suppressed by 4-PBA administration. Increased expression of glial fibrillary acidic protein denoted retinal neuroinflammation, and inflammatory cytokines were induced after light exposure; however, 4-PBA acted as an anti-inflammatory. Suppression of ER stress by 4-PBA may be a new therapeutic approach to suppress the progression of retinal neurodegeneration and protect visual function against photo-stress.

• Publisher: MDPI AG,MDPI
• Subject: Apoptosis / B-cell lymphoma / Bax protein / Bcl-2 protein / Bcl-x protein / CCAAT/enhancer-binding protein / Cytokines / death / Diabetic retinopathy / Endoplasmic reticulum / endoplasmic reticulum stress / Ethanol / Experiments / Glial fibrillary acidic protein / Heme / heme oxygenase (biliverdin-producing) / histology / Homeostasis / Hypoxia / immunoglobulin heavy chains / Inflammation / Light / light-induced retinal damage / Lymphocytes B / Mitochondria / Neurodegeneration / neurodegenerative diseases / Neuronal-glial interactions / Neuroprotection / neuroprotective effect / Optic nerve / Oxidative stress / Oxygenase / Phenylbutyric acid / photoreceptors / Retina / Retinal degeneration / stress response / therapeutics / Visual perception