Retinal gene and pathway modulation by benzathine penicillin: A potential link to Extensive Macular Atrophy with Pseudodrusen (EMAP) and neurodegeneration.

Abstract

Extensive Macular Atrophy with Pseudodrusen (EMAP) is a rare and rapidly progressive retinal disease marked by central vision loss, chorioretinal atrophy, and pseudodrusen, primarily affecting middle-aged individuals. Recent studies have identified a statistically significant association between long-term use of benzathine penicillin (BP) and the onset of EMAP. However, the molecular mechanisms underlying this relationship remain unclear. In this study, we performed an integrative in silico analysis to explore the genes modulated by BP that are expressed in ocular tissues and involved in retinal metabolic pathways. Using public databases (PubChem, GTEx, HPA, EYEDB), we identified 52 BP-responsive genes, with six (CD4, CRP, IL6, IL1R1, TAC1, TNF) directly modulated by BP and expressed in the retina. These genes are implicated in inflammation, immune response, and retinal homeostasis. Expression data show strong presence in eye and brain tissues, and several are associated with age-related macular degeneration (AMD). Network analysis revealed gene-gene and protein-protein interactions, highlighting a shared pathophysiological axis. Notably, IL6 and TNF are involved in oxidative stress, endoplasmic reticulum stress, and chronic inflammation--hallmarks of both EMAP and atrophic AMD. Our findings suggest that BP may induce EMAP by dysregulating retinal genes involved in neurodegeneration, providing new insights into drug safety and retinal disease mechanisms.