A NOVEL DOPAMINE AGONIST WITH NEUROPROTECTIVE EFFECT

DIEGO PLOPER; AGUSTÍN O. PERNICONE; VERONICA MANZANO; BENJAMÍN SOCIAS; CESAR LUIS AVILA; ESTEBAN VERA PINGITORE; ANALIA SILVINA CHAVES; ADRIANA A. KOLENDER; RODRIGO TOMAS-GRAU; FLORENCIA GONZALEZ LIZARRAGA; MARTIN LUOUNG; OSCAR VARELA; CHEHÍN ROSANA

Paris

Congreso; Federation of European Neuroscience Societies (FENS); 2022

Aims: Continuous and safe delivery of dopamine (DOPA) across the blood brain barrier (BBB) is a main obstacle for successful substitution therapy in Parkinson´s disease. Our aim is to take advantage of the well-known capacity of doxycycline (DOXY) to cross the BBB, together with its neuroprotective activity, in order to obtain a DOXY-DOPA hybrid molecule, which we call Pegasus, with potential application in Parkinson´s disease.Methods: Pegasus was synthetized by removing the dimethylamino at C4 and introducing an amino group at C9, which was covalently coupled to dopamine through a linker. Confirmation of intact dopaminergic receptor activation was performed with cAMPNOMAD cells (INNOPROT). Cytotoxicity was studied with the MTT assay in SH-SY5Y and Bv2 cells, and with HEK293T Cytochrome C-tGFP apoptosis reporter cell line (INNOPROT). Neuroprotective properties were studied as follows: i) inhibition of α-Synuclein (α-Syn) aggregation by ThT assay; ii) antioxidant capability by using CellRoxTM reagent; iii) inhibition of proinflammatory cytokine IL-1β release by microglial cells; iv) influence on lysosomal number in SH-SY5Y cells with LysoTrakerTM.