CONICET | Buscador de Institutos y Recursos Humanos

Parkinson?s disease related death of dopaminergic neurons has been linked to pathological aggregation of alpha-synuclein protein and its transcellular traffic through the dopaminergic system. Tetracyclines, such as minocycline and doxycycline have been shown to be neuroprotective in Parkinson?s disease animal models. Neuroprotective activities of minocycline have been attributed to its inhibitory effects on microglia activation. On the other hand, doxycycline has been shown to protect cells by inhibiting the formation of toxic alpha synuclein species. However, the antibiotic activity of these compounds limit their prescription for chronic treatments such as neurodegenerative disorders. Thus, chemically modified tetracyclines with diminishing or reduced antibiotic activity could represent a more adequate therapy for long-term treatments. In this regard, it was recently reported that the chemically modified tetracycline lacks antibiotic activity but retains anti-inflammatory effects. In the present study we evaluate the ability of CMT inhibit alpha-synuclein aggregation using different biophysical techniques such as fluorescence techniques, SAXS and advanced microscopies. In addition, we evaluate the ability of CMT to modulate the inflammatory response of microglial cultures mediated by different inflammogenic compounds and we demonstrate that CMT inhibits cytokine production and Iba-1 release, as well as expression of prototypical markers of microglial activation. Considering that incyclinide has reduced antibiotic activity compared to other tetracyclines and is a well tolerated drug according to cancer-related Phase I clinical trials, we conclude that it could be a ?ready to use drug?. Due to its ability to diminish toxic aggregation of alpha synuclein as well as neuroinflammatory processes, we propose CMT is poised as an promising candidate for Phase I clinical trials in neuroprotection.

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