Doble Reduced Demeclocycline Derivative: a promising new molecule with neuroprotective effects

TOMAS GRAU, RH; GONZALEZ LIZARRAGA, MF; PLOPER, D; AVILA, CÉSAR L.; SOCIAS, B; BESNAULT, P; TOURVILLE, A; ROSE, CLÉMENCE; SEON-MÉNIEL, BLANDINE; BRUNEL, JM; FERRIE, L; RAISMAN VOZARI, R; MICHEL, PATRICK P.; FIGADERE, B; CHEHÍN, R

Rosario

Congreso; L Reunión Anual de la Sociedad Argentina de Biofísica; 2022

Sociedad Argentina de Biofísica

The ability of doxycycline (DOX) and demeclocycline (DMC) to rescue α-synuclein (α-Syn)fibril-induced pathology has been previously reported, positioning these tetracyclines(TCs) as potential neuroprotective compounds for synucleinopathies. However, theirantibiotic activity precludes their potential use in long-term treatments. Therefore, wehave synthesized more than 20 novel TC derivatives without antimicrobial activity andscreened, by ThT fluorescence spectroscopy, for ability for inhibit the α-Syn amyloidaggregation. A doubly reduced DMC, referred to as DDMC, exhibited the highest α-Synantiaggregant activity. Chemically, the molecule was obtained by removal thedimethylamino substituent at position 4 and the reducing of the hydroxyl group atposition 12a on ring A of DMC. These modifications strongly diminished the antibioticactivity against Gram-positive and Gram-negative bacteria. The inhibition of α-Synaggregation was complemented by Congo Red assays and transmission electronmicroscopy (TEM) analysis. This novel TC preserved the low toxicity of its precursor DMCon dopaminergic cell lines according to MTT colorimetric assay. Furthermore, DDMCreduced the seeding activity of α-Syn preformed fibrils (α-SynPFF) in biophysical assaysas well as in a transgenic dopaminergic cell model overexpressing α-Syn-tRFP. In addition,the anti-inflammatory potential of DDMC was tested in microglial primary cell cultures byusing α-SynPFF as an inflammatory trigger. In the presence of the novel compound, (αSynPFF+DDMC) a significant reduction of TNFα and Glutamate release was observed. Onthe other hand, fibrils formed in the presence of DDMC (α-SynPFF:DDMC) were less proneto induce proinflammatory factors than control α-SynPFF. Our results suggest that DDMCmay be a promising drug candidate in drug development pipelines for Parkinson’s diseaseand other synucleinophathies.