DOXYCYCLINE CAN EFFICIENTLY SWITCH ALPHA-SYNUCLEIN EARLY AGGREGATION OLIGOMERS INTO NON-TOXIC SPECIES: REPURPOSING AN OLD DRUG AS NEUROPROTECTOR

R. CHEHIN ; D.B. ELAINE; L. BARBOSA; F. GONZALEZ LIZARRAGA; D. PAPY-GARCIA; J. SEPULVEDA DIAZ; C. AVILA; R. RAISMAN-VOZARI; C. FERNANDEZ; B. ANDRES; B. SOCIAS

Congreso; Neurotoxicity Society; 2017

AimsSynucleinophaties are progressive disorders with no cure to date. An attractive strategy to tackle this problem is discovering new uses for approved drugs to provide the quickest possible transition from bench to bedside.MethodWe used a combination biophysical techniques like fluorescence and infrared spectroscopy, electronic microscopy, small angle X Ray scattering and NMR together with cellular biology approaches to assess the impact of doxycycline on α-synuclein aggregation.ResultsWe demonstrate the ability of doxycycline to interfere with the pathologic cycle involved in synucleinopathies at the aggregation level. We proved that doxycycline interacts with alpha-synuclein early aggregation intermediates leading to the formation of off-pathway species, with parallel beta-sheet content, that do not evolve into fibril formation. These aggregates are neither cytotoxic to dopaminergic cell lines, nor capable of disrupting the integrity of liposomes membrane. Furthermore, doxycycline is also able to block the seeding capacity of alpha-synuclein preformed aggregates.ConclusionThis novel mechanism of action proposed for doxycycline might act in a synergistic way with its anti- inflammatory and antioxidant properties to exert neuroprotection on animal models in vivo. Moreover, administration of doxycycline at subantibiotic doses would deliver a concentration high enough in the brain to interfere with the production of α-synuclein toxic species. These results place doxycycline as a pleiotropic drug becoming an attractive therapeutic strategy against synucleinopathies.