Modulation of A2aAR with selective antagonists to control inflammation in Parkinson’s disease

Parkinson’s Disease (PD) represents the second most common neurodegenerative disorder worldwide and a health concern in ageing societies. Available treatments possess only symptomatic action and severe long-term side effects, and the research for developing neuroprotective strategies is urgent. It is widely demonstrated that neuroinflammation is a key event in PD, especially in the disease progression. Neuroinflammation is driven by brain resident immune cells like astroglia and microglia. Dysregulation of these cells leads to abnormal release of inflammatory cytokines like tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), interferon-γ (IFN-γ) and the increase of oxygen reactive species (ROS) 1. Thus, the modulation of pathological immune response could be a crucial process to slow down the disease progression. Microglial cells can be activated by adenosine through the interaction with A2A adenosine receptors (A2AAR). Indeed, the modulation of purinergic receptors has been associated with a slower degeneration of nigrostriatal dopaminergic cells in PD 2. A2AAR antagonist 8-ethoxy-9-ethyladenine (ANR94) showed to protect nigrostriatal neurons from neuroinflammation in an animal model of PD 3, so aim of this project was to test several ad hoc-designed A2AAR antagonists (ANR94 analogues) with improved pharmacodynamic and pharmacokinetic properties, on BV-2 microglial cells activated with 100 ng/mL LPS for 24 h. The newly synthetized compounds chosen for further characterization were thirteen. The potential anti- inflammatory activity of ANR94 analogues was evaluated by measuring the release of NO in the culture medium by Griess reagent, while gene expression analyses of inflammatory cytokines IL-1β and TNF- α, and the pro-inflammatory enzymes iNOS and COX-2 were performed by RT-PCR. Interestingly, among the newly synthetized compounds, that identified with the number 13 would seem to be the most promising in counteracting inflammatory damage suggesting its potential use as therapeutic agent to prevent/counteract PD. Of course, animal and clinical studies are needed to investigate its in vivo activity. This research was supported by the University of Camerino (FAR2019, Grant no. FPI000051).