Repositioning doxycycline for treating synucleinopathies: Evidence from a pre-clinical mouse model

Background and purpose: Parkinson's disease remains orphan of valuable therapies capable to interfere with the disease pathogenesis despite the large number of symptomatic approaches adopted in clinical practice to manage this disease. Treatments simultaneously affecting alpha-synuclein (alpha-syn) oligomerization and neuroinflammation may counteract Parkinson's disease and related disorders. Recent data demonstrate that Doxycycline, a tetra-cycline antibiotic, can inhibit alpha-syn aggregation as well as neuroinflammation. We herein investigate, for the first time, the potential therapeutic properties of Doxy in a human alpha-syn A53T transgenic Parkinson's disease mouse model evaluating behavioural, biochemical and histopathological parameters. Experimental approach: Human alpha-syn A53T transgenic mice were treated with Doxycycline (10 mg/kg daily ip) for 30 days. The effect of treatment on motor, cognitive and daily live activity performances were examined. Neuropathological and neurophysiological parameters were assessed through immunocytochemical, electro-physiological and biochemical analysis of cerebral tissue. Key results: Doxy treatment abolished cognitive and daily life activity deficiencies in A53T mice. The effect on cognitive functions was associated with neuroprotection, inhibition of alpha-syn oligomerization and gliosis both in the cortex and hippocampus. Doxy treatment restored hippocampal long-term potentiation in association with the inhibition of pro-inflammatory cytokines expression. Moreover, Doxy ameliorated motor impairment and reduced striatal glial activation in A53T mice. Conclusions and implications: Our findings promote Doxy as a valuable multi-target therapeutic approach coun-teracting both symptoms and neuropathology in the complex scenario of alpha-synucleinopathies.