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 thedisease pathogenesis despite the large number of symptomatic approaches adopted in clinical practice to managethis disease. Treatments simultaneously affecting α-synuclein (α-syn) oligomerization and neuroinflammationmay counteract Parkinson’s disease and related disorders. Recent data demonstrate that Doxycycline, a tetracyclineantibiotic, can inhibit α-syn aggregation as well as neuroinflammation. We herein investigate, for the firsttime, the potential therapeutic properties of Doxy in a human α-syn A53T transgenic Parkinson’s disease mousemodel evaluating behavioural, biochemical and histopathological parameters.Experimental approach: Human α-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, electrophysiologicaland biochemical analysis of cerebral tissue.Key results: Doxy treatment abolished cognitive and daily life activity deficiencies in A53T mice. The effect oncognitive functions was associated with neuroprotection, inhibition of α-syn oligomerization and gliosis both inthe cortex and hippocampus. Doxy treatment restored hippocampal long-term potentiation in association withthe inhibition of pro-inflammatory cytokines expression. Moreover, Doxy ameliorated motor impairment andreduced striatal glial activation in A53T mice.Conclusions and implications: Our findings promote Doxy as a valuable multi-target therapeutic approach counteractingboth symptoms and neuropathology in the complex scenario of α-synucleinopathies.