PEGASUS: A NOVEL DOPAMINE AGONIST WITH NEUROPROTECTIVE EFFECT

CHEHIN, ROSANA; PERNICONE, AGUSTIN; MANZANO, VERÓNICA E.; VERA PINGITORE, ESTEBAN; LUONG, MARTIN; AVILA, CESAR; KOLENDER, ADRIANA; GONZALEZ LIZARRAGA, FLORENCIA; TOMAS GRAU, RODRIGO; CHAVES, SILVINA; VARELA, OSCAR; PLOPER, DIEGO

Paris

Congreso; FENS Forum 2022; 2022

Aims: continuous and safe delivery of dopamine across the blood brain barrier (BBB) is a main obstacle for successful substitution therapy in Parkinson's disease. However, the presence of the neurotransmitter does not interfere the progression of neuronal death. Our aim is taking advantage of the well-known capacity of doxycycline (DOXY) to cross the BBB together with its neuroprotective activity to obtain a DOXY-DOPA hybrid molecule that we call Pegasus. Methods: Pegasus was synthetized by removal of the dimethylamino function at C4 and introducing an amino group at C-9, which was covalentlylinked via a linker to dopamine. Activation of dopaminergic receptors was performed by cAMPNOMAD Cells (Innoprot). Cytotoxicity was studied by MTT assay in SH-SY5Y/Bv2 cell lines. Neuroprotective properties were studied asfollows: i) inhibition of α-Synuclein (AS) aggregation by ThT assay; ii) antioxidant capability by CellRoxTM assay; iii) inhibition of proinflammatory cytokine IL-1β release by microglial cells; iv) antiapoptotic properties on HEK293T Cytochrome C-tGFP cell line, and v) influence on lysosomal biogenesis in SH-SY5Y cells with LysoTrakerTM assay. Results and conclusion: Pegasus activated dopaminergic receptors 10-fold less efficiently than dopamine but resulted in improved theoretical ability to cross the BBB. Pegasus did not show toxicity in two different cell lines, and efficiently inhibited AS amyloid aggregation as well as LPS or AS fibrils-induced neuroinflammation. The new molecule also preserved antioxidant properties, characteristic of tetracyclines, and did not interfere with lysosomes biogenesis. We present Pegasus as a dopamine agonist with neuroprotective activity, and an ideal candidate for further preclinical studies.