Inhibiting thrombin improves motor function and decreases oxidative stress in the LRRK2 transgenic Drosophila melanogaster model of Parkinson's disease

摘要

Parkinson's disease (PD) is a complex neurodegenerative disease characterized by the presence of tremors, loss of dopaminergic neurons and accumulation of alpha-synuclein. While there is no single direct cause of PD, genetic mutations, exposure to pesticides, diet and traumatic brain injury have been identified as risk factors. Increasing evidence suggests that oxidative stress and neuroinflammation contribute to the pathogenesis of neuronal injury in neurodegenerative diseases such as PD and Alzheimer's disease (AD). We have previously documented that the multifunctional inflammatory mediator thrombin contributes to oxidative stress and neuroinflammation in AD. Here, for the first time, we explore the role of thrombin in a transgenic PD model, the LRRK2 mutant Drosophila melanogaster. Transgenic flies were treated with the direct thrombin inhibitor dabigatran for 7 days and locomotor activity and indices of oxidative stress evaluated. Our data show that dabigatran treatment significantly (p < 0.05) improved climbing activity, a measurement of locomotor ability, in male but had no effect on locomotor performance in female flies. Dabigatran treatment had no effect on tyrosine hydroxylase levels. Analysis of oxidative stress in male flies showed that dabigatran was able to significantly (p < 0.01) lower reactive oxygen species levels. Furthermore, Western blot analysis showed that the pro-oxidant proteins iNOS and NOX4 are elevated in LRRK2 male flies compared to wildtype and that treatment with dabigatran reduced expression of these proteins. Our results indicate that dabigatran treatment could improve motor function in PD by reducing oxidative stress. These data suggest that targeting thrombin may improve oxidative stress related pathologies in PD. (C) 2020 Elsevier Inc. All rights reserved.