Potential neuroprotective effect of DDox in Parkinson's disease models: A novel non-antibiotic doxycycline derivative with alpha-Synuclein anti-aggregating properties

MARÍA DEL MILAGRO TERÁN; TOMAS-GRAU, RODRIGO; SOLIZ SANTANDER, ESTEFANÍA; LUNA MERCADO, ÁLVARO; ÁVILA, CÉSAR; RAISMAN-VOSARI, R.; FIGADÈRE, B.; PLOPER, DIEGO; CHEHÍN, ROSANA

San Luis

Congreso; XXXVIII Annual meeting of the SAN; 2023

Sociedad Argentina de Investigación en Neurociencias

Parkinson´s disease (PD) is a chronic neurodegenerative disorder characterized by the loss of dopaminergic neurons due to misfolding and aggregation of a-synuclein (aS) protein. These toxic aggregates disrupt normal cellular processes, leading to neuronal dysfunction and death. Although previous reports indicate that doxycycline (DOX) has the potential to interfere with aS aggregation, its antibiotic activity confers a limitation for long-term treatments. Here, we synthesized and tested a novel reduced form of DOX (DDox), with diminished antibacterial activity. DDox exhibited an enhanced and dose-dependent anti-aggregating effect against aS. Additionally, DDox showed no toxicity in SH-SY5Y cell lines. Moreover, in transgenic SH-SY5Y-aS-RFP cells where endogenous aS aggregates were induced by treatment with exogenous pre-formed aS fibrils (aS PFF), co-treatment with DDox reduced αS seeding. However, the same effect was not observed when DDox was used as a pre-treatment, suggesting a direct effect on aS PFF. Remarkably, DDox inhibited fluorescentlly-labeled aS PFF uptake and aS PFF-triggered lysosomal stress, which represent novel properties for tetracyclines in PD models. Our results suggest that DDox is a non-toxic molecule with non-antibiotic activity and neuroprotective properties, which make it attractive for in vivo preclinical PD studies.