Targeting TSPO Reduces Inflammation and Apoptosis in an In Vitro Photoreceptor-Like Model of Retinal Degeneration

Area of Science:

• Neuroscience
• Ophthalmology
• Pharmacology

Background:

• The 18 kDa translocator protein (TSPO) is a mitochondrial protein implicated in cellular processes and upregulated in CNS neuropathologies.
• TSPO expression in retinal cells and its role in neurodegeneration are not well-understood.
• Inflammation is a key driver of retinal neurodegenerative diseases leading to vision loss.

Purpose of the Study:

• To investigate TSPO expression in a photoreceptor-like cell line (661W).
• To evaluate the therapeutic potential of TSPO ligands, specifically N,N-dialkyl-2-arylindol-3-ylglyoxylamides (PIGAs), in an in vitro model of inflammatory retinal degeneration.
• To explore the mechanism of action of PIGA compounds in protecting retinal cells.

Main Methods:

• Assessed TSPO expression in 661W cells.
• Utilized an in vitro model of lipopolysaccharide (LPS)-induced degeneration in 661W cells.
• Tested the anti-inflammatory and cytoprotective effects of various PIGA compounds and the reference ligand PK11195.
• Investigated the role of neurosteroids by using the pregnenolone synthesis inhibitor SU-10603.

Main Results:

• TSPO expression was confirmed in 661W photoreceptor-like cells.
• All tested PIGA compounds demonstrated anti-inflammatory and cytoprotective effects against LPS-induced damage.
• PIGA-mediated protection was diminished by SU-10603, indicating the involvement of neurosteroids.
• PIGAs modulated inflammatory and apoptotic pathways in the stressed cells.

Conclusions:

• Targeting TSPO with PIGA ligands represents a potential therapeutic strategy for inflammatory retinal neurodegeneration.
• PIGA compounds offer cytoprotection and anti-inflammatory benefits in photoreceptor-like cells.
• Neurosteroid pathways appear to mediate the protective effects of TSPO ligands in this model.