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

TERÁN, MM; TOMAS GRAU, RH; SOLIZ SANTANDER, SE; LUNA MERCADO, A; AVILA, CÉSAR L.; RAISMAN VOZARI, R; FIGADÈRE, B; PLOPER, D; CHEHÍN, R

San Luis

Congreso; XXXVIII Annual Meeting of the SAN; 2023

Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by theloss of dopaminergic neurons due to misfolding and aggregation of a-synuclein (aS)protein. These toxic aggregates disrupt normal cellular processes, leading to neuronaldysfunction and death. Although previous reports indicate that doxycycline (DOX) hasthe potential to interfere with aS aggregation, its antibiotic activity confers a limitationfor 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 inSH-SY5Y cell lines. Moreover, in transgenic SH-SY5Y-aS-RFP cells where endogenous aSaggregates were induced by treatment with exogenous pre-formed aS fibrils (aS PFF),co-treatment with DDox reduced αS seeding. However, the same effect was notobserved 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-triggeredlysosomal stress, which represent novel properties for tetracyclines in PD models. Ourresults suggest that DDox is a non-toxic molecule with non-antibiotic activity andneuroprotective properties, which make it attractive for in vivo preclinical PD studies.