Endoplasmic reticulum stress as an underlying factor in leading causes of blindness and potential therapeutic effects of 4-phenylbutyric acid: from bench to bedside

ABSTRACT

Introduction

Mounting evidence has emerged showing that endoplasmic reticulum (ER) stress participates in triggering cell injuries in ocular tissues, manifested as disorders such as cataracts, age-related macular degeneration, glaucoma, and diabetic retinopathy.

Areas covered

ER stress is a condition in which the ER is perturbed by the accumulation of unfolded and misfolded proteins. In a dynamic signaling cascade, the unfolded protein response (UPR) is triggered by three ER-transmembrane stress sensors to restore homeostasis and cell survival, however, if it fails, the cell will undergo a sustained ER stress condition which deteriorates cell function and promote cell death. Sustained ER stress is shown to contribute in a wide range of diseases including ophthalmologic disorders. Targeting ER stress by inhibitor agents might have promising therapeutic implications in treating eye disorders. The current review summarizes the results of the latest studies in support of the potential therapeutic utility of 4-phenylbutyric acid (4-PBA), an FDA approved ER stress inhibitor, in disorders leading to permanent vision loss.

Expert opinion

The therapeutic potential of 4-PBA in ophthalmic diseases is strongly supported by many experimental studies. Safety and efficacy studies of intravitreal injection of 4-PBA and other ER stress by inhibitors, are lacking.

KEYWORDS:

• ER stress
• 4-phenylbutyric acid
• cataract
• Age-related macular degeneration
• glaucoma
• diabetic retinopathy

Acknowledgments

The authors are grateful to the Eye Research Center, Rasoul Akram Hospital, Iran University of Medical Sciences; and Neurophysiology Research Center; Shahid Beheshti University of Medical Sciences; for support of this work, in collaboration.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary Material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17469899.2022.2145945

Additional information

Funding

This paper was not funded.