Novel Findings on CCR1 Receptor in CNS Disorders: A Pathogenic Marker Useful in Controlling Neuroimmune and Neuroinflammatory Mechanisms in Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is recognized as the second most common neurodegenerative disease worldwide. Even if PD etiopathogenesis is not yet fully understood, in recent years, it has been advanced that a chronic state of inflammation could play a decisive role in the development of this pathology, establishing the close link between PD and neuroinflammation. In the broad panorama of inflammation and its several signaling pathways, the C-C chemokine receptor type 1 (CCR1) could play a key pathogenic role in PD progression, and could constitute a valuable target for the development of innovative anti-PD therapies. In this study, we probed the neuroprotective properties of the CCR1 antagonist BX471 compound in a mouse model of MPTP-induced nigrostriatal degeneration. BX471 treatments were performed intraperitoneally at a dose of 3 mg/kg, 10 mg/kg, and 30 mg/kg, starting 24 h after the last injection of MPTP and continuing for 7 days. From our data, BX471 treatment strongly blocked CCR1 and, as a result, decreased PD features, also reducing the neuroinflammatory state by regulating glial activation, NF-κB pathway, proinflammatory enzymes, and cytokines overexpression. Moreover, we showed that BX471’s antagonistic action on CCR1 reduced the infiltration of immune cells, including mast cells and lymphocyte T activation. In addition, biochemical analyses carried out on serum revealed a considerable increase in circulating levels of CCR1 following MPTP-induced PD. In light of these findings, CCR1 could represent a useful pathological marker of PD, and its targeting could be a worthy candidate for the future development of new immunotherapies against PD.