Parkinson’s Disease (PD) is the second most common neurodegenerative disorder worldwide and represents an important health concern in ageing societies. State-of-the-art treatments have mere symptomatic action and severe long-term side effects, strongly urging the quest for the development of neuroprotective therapies. Growing evidence indicates that neuroinflammation, mediated by microglia and astroglia, plays a crucial role in PD. Although it is still unclear whether the neuroimmune response may represent a primary cause for neuronal loss, there is wide consensus on its involvement in disease progression. Adenosine receptors, expressed in microglial and astroglial cells, modulate inflammatory response in PD. The preliminary data suggest that A2A adenosine receptor (A2AARs) antagonists may have therapeutic efficacy. Given these premises, the main goal of the present project is to test the neuroprotective efficacy of a novel, ad hoc-designed A2AAR antagonists in activated microglial cells and two distinct animal models of the disease with complementary characteristics. As a secondary goal, we will evaluate the ability of A2AAR antagonists to modulate microglial and astroglial response in vivo. In addition to the translational significance, the results of this research have the potential to advance our knowledge of the complex role played by the inflammatory response in parkinsonian neurodegeneration.