Repositioning Doxycycline for treating Parkinson’s Disease: evidence from a pre-clinical mouse model

Background 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 α-synuclein (α-syn) oligomerization and neuroinflammation may counteract Parkinson’s disease. Recent data demonstrated that Doxycycline an antibiotic of the tetracycline class, can inhibit α-syn aggregation and exert anti-inflammatory activity. We herein investigate, for the first time, the potential therapeutic properties of Doxy in a human α-syn A53T transgenic Parkinson’s disease mouse model by the evaluation of behavioural, biochemical and histopathological parameters. Methods human α-syn A53T transgenic mice were treated with Doxycycline (10 mg/Kg daily ip) for 30 days, the effect of treatment on motor and cognitive behaviour impairment and daily live activity of mice were examined, successively immunocytochemical, electrophysiological and biochemical analysis of cerebral tissue was performed. Results Doxy treatment abolished cognitive and daily life activity deficiencies in A53T mice. The effect on cognitive functions was associated with neuroprotection, inhibition of α-syn oligomerization and gliosis both in the cortex and hippocampus. Doxy treatment restored hippocampal long-term potentiation in association with inhibition of pro-inflammatory cytokines expression. Moreover, Doxy ameliorated motor impairment and reduced striatal glial activation in A53T mice. Conclusions Our findings promote Doxy as a valuable multi-target therapeutic approach counteracting both symptoms and neuropathology in the complex scenario of α-synucleinopathies