Purines have key roles in neurotransmission and neuromodulation, with their effects being mediated by the purine and pyrimidine receptor subfamilies, P1, P2X and P2Y. Recently, purinergic mechanisms and specific receptor subtypes have been shown to be involved in various pathological conditions including brain trauma and ischaemia, neurodegenerative diseases involving neuroimmune and neuroinflammatory reactions, as well as in neuropsychiatric diseases, including depression and schizophrenia. This article reviews the role of purinergic signalling in CNS disorders, highlighting specific purinergic receptor subtypes, most notably A(2A), P2X(4) and P2X(7), that might be therapeutically targeted for the treatment of these conditions.

Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system (CNS), which causes demyelination of axons. Experimental autoimmune encephalomyelitis (EAE) is a mouse model of MS that is induced by immunizing mice with myelin oligodendrocyte glycoprotein (MOG). The best-known treatment for MS is the type I interferon (IFN), IFN-β; however, its mechanism of action is unclear. Prinz et al. found that the abundance of IFN-β was increased in the CNS of MOG-treated mice compared with untreated mice, as measured by enzyme-linked immunosorbent assays, suggesting that local, but not systemic, IFN-β abundance is important in this disease. Treatment of mice deficient in the type I IFN receptor (Ifnar–/– mice) with MOG resulted in worse disease and increased mortality compared with MOG-treated wild-type mice. Histological examination revealed that MOG-treated Ifnar–/– mice had more infiltrating myeloid cells, which included macrophages and microglia, in their spinal cords than did MOG-treated wild-type mice. The authors bred strains of mice that were Ifnar-deficient in specific cell types and exposed them to MOG. Whereas deletion of Ifnar in CD4+ T cells, B cells, astrocytes, or oligodendrocytes had little or no effect on disease outcome, deletion of Ifnar in myeloid cells led to exacerbated disease and increased mortality compared with that in wild-type mice. This was associated with the increased uptake of degraded myelin protein by Ifnar-deficient myeloid cells and the increased abundance of the proinflammatory cytokine tumor necrosis factor-{alpha} and the chemokine CCL2, which recruits myeloid cells. As Axtell and Steinman discuss, this study suggests that IFN-β acts on myeloid cells in the CNS to suppress inflammation and the processing of antigenic peptides, which would otherwise exacerbate disease by activating infiltrating T cells and causing further inflammation.