V-110 | Screening of novel chemically modified tetracyclines against Parkinson’s Disease.

Neurochemistry and Neuropharmacology
Author: María Laura Guayán | Email: mlauraguayan@gmail.com

María Laura Guayán^1°, Rodrigo Tomas-Grau^1°,Rita Raisman-Vozari^2°, Bruno Figadère^3°, Rosana Chehín^1°, Diego Ploper^1°

^1° Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET-UNT-Ministerio de Salud Pública de Tucumán), Pasaje Dorrego 1080, 4000, San Miguel de Tucumán, Argentina
^2° Paris Brain Institute-ICM, Inserm, Sorbonne Université, CNRS, Hôpital Pitié Salpêtrière, 75013 Paris, France
^3° BioCIS, CNRS, Université Paris Saclay, 92290 Châtenay-Malabry, France

Tetracyclines (TCs) can inhibit protein aggregation, reduce inflammation, and protect dopaminergic neurons, suggesting they might slow or prevent the progression of Parkinson’s disease (PD). However, their antibiotic activity limits their repurposing for this condition. Therefore, six novel non-antibiotic TCs were synthesized and screened to identify those with the most promising neuroprotective properties. Initially, their antibiotic activity was assessed. Viability assays were then conducted in SH-SY5Y cells, and their effects on α-synuclein (αS) aggregation, a key mechanism in PD pathogenesis, were studied. The most promising molecules were selected, and αS species formed in the presence of these compounds were characterized using dynamic light scattering and transmission electron microscopy. Additionally, the retention of antioxidant properties of TCs was tested. Finally, using a SH-SY5Y-αS-tRFP transgenic cell line with fluorescently labeled αS preformed fibrils (PFFαS-488), the ability of these compounds to inhibit fibril uptake and subsequent intracellular seeding was evaluated. Results showed that all molecules inhibited αS aggregation, with the aggregated species being morphologically distinct from control fibrils. The most promising compounds showed no toxicity in SH-SY5Y cells, exhibited antioxidant activity, and reduced PFF uptake. These findings identify potential candidates for further investigation in PD, targeting several underlying pathological mechanisms.