Date of Award

6-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Track

Pharmaceutics

Research Advisor

Nawajes Mandal, PhD

Committee

Dr. Hassan Almoazen; Dr. Harry Kochat; Dr. Santosh Kumar; Dr. Soumyajit Majumdar; Dr. Bernd Meibohm

Keywords

Retinal degenerative diseases; Ceramide; L-Cycloserine; Photoreceptor cell death; Oxidative stress; Therapeutic intervention; Ophthalmic delivery; Hydrogels; Sustained release; Biopolymer

Abstract

Retinal degenerative diseases, affecting millions worldwide, are caused by irreversible photoreceptor cell death. These conditions lead to irreversible vision loss or blindness, presenting significant economic challenges. Retinal degenerative diseases result from a complex interplay of genetic and environmental factors, such as light exposure and oxidative stress. Effective treatments are currently limited, which underscores the urgent need for comprehensive solutions. Ceramide, a bioactive sphingolipid, has emerged as a pivotal mediator in the apoptotic cascade associated with retinal degeneration, presenting a promising target for therapeutic intervention. This research explores the therapeutic potential of L-Cycloserine, a small molecule inhibitor of de novo ceramide biosynthesis, in protecting against retinal degeneration. The first section investigates the protective effect of L-Cycloserine against oxidative stress-induced retinal cell death using a mouse photoreceptor-derived cell line, 661W. Results demonstrate that L-Cycloserine significantly protects 661W cells from oxidative stress by reducing bioactive ceramide levels, thereby mitigating cell death under oxidative stress conditions. Molecular assays further elucidate the mechanism underlying the protective action of L-Cycloserine, highlighting its modulation of antioxidant and apoptotic pathways. In the second section, the efficacy of L-Cycloserine in protecting against light-induced retinal damage is evaluated using albino BALB/c mice. Systemic administration of L-Cycloserine before light exposure significantly prevents photoreceptor cell death, preserving retinal function and morphology. Biodistribution studies confirm the presence of L-Cycloserine in target tissue, the retina, while sphingolipid analysis reveals its role as a ceramide biosynthesis inhibitor. These findings underscore the potential of L-Cycloserine as a therapeutic candidate for retinal degenerative diseases. The final section focuses on the development of in-situ hydrogels for topical ophthalmic delivery of L-Cycloserine, addressing the challenges of drug delivery to the posterior segment of the eye. Electrolyte-stimulated biopolymer-based hydrogels demonstrate sustained release of L-Cycloserine and maintain high corneal permeability, offering a promising platform for the ocular delivery of this drug. Lyophilization and stability studies highlight the feasibility of long-term storage, paving the way for further optimization and clinical translation. Collectively, this research provides comprehensive insights into the therapeutic potential of targeting ceramide biosynthesis with L-Cycloserine for the treatment of retinal degenerative diseases. This research addresses critical gaps in current therapeutic options and offers innovative solutions, including topical delivery of L-Cycloserine, to avoid systemic exposure. It lays the groundwork for developing novel therapies to combat vision loss associated with retinal degenerative diseases.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

ORCID

https://orcid.org/0000-0002-6352-3875

DOI

10.21007/aetd.cghs.2024.0007

Additional Files
2024-007-Tahia-AETD-DOA.pdf (207 kB)
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