Chemically modified tetracycline (CMT) inhibits alpha-synuclein amyloid fibers formation and neuroinflammation|

GONZALES LIZARRAGA, MF; SOCIAS, S.B.; AVILA C.; PLOPER D.; BARBOSA L.; ITRI R.; PIETRASANTA L.; RAISMAN VOZARI R.; CHEHÍN R.

San Diego

Congreso; Neuroscience 2018; 2018

Society for Neuroscience (USA)

Parkinson?s disease related death of dopaminergic neurons has been linked topathological aggregation of alpha-synuclein protein and its transcellular tra􀃕cthrough the dopaminergic system. Tetracyclines, such as minocycline anddoxycycline have been shown to be neuroprotective in Parkinson?s disease animalmodels. Neuroprotective activities of minocycline have been attributed to itsinhibitory e􀃗ects 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 modi􀃒ed 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 modi􀃒ed tetracycline lacks antibiotic activity but retains anti-in􀃓ammatory e􀃗ects. In the present study we evaluate the ability of CMT inhibit alpha-synuclein aggregation using di􀃗erent biophysical techniques such as 􀃓uorescence techniques, SAXS and advanced microscopies. In addition, we evaluate the ability of CMT to modulate the in􀃓ammatory response of microglial cultures mediated by di􀃗erent in􀃓ammogenic 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 neuroin􀃓ammatory processes, we propose CMT is poised as an promising candidate for Phase I clinical trials in neuroprotection.