Supportive or detrimental roles of P2Y receptors in brain pathology?—The two faces of P2Y receptors in stroke and neurodegeneration detected in neural cell and in animal model studies

Abstract

This review describing the role of P2Y receptors in neuropathological conditions focuses on obvious differences between results demonstrating either a role in neuroprotection or in neurodegeneration, depending on in vitro and in vivo models. Such critical juxtaposition puts special emphasis on discussions of beneficial and detrimental effects of P2Y receptor agonists and antagonists in these models. The mechanisms reported to underlie the protection in vitro include increased expression of oxidoreductase genes, like carbonyl reductase and thioredoxin reductase; increased expression of inhibitor of apoptosis protein-2; extracellular signal-regulated kinase-and Akt-mediated antiapoptotic signaling; increased expression of Bcl-2 proteins, neurotrophins, neuropeptides, and growth factors; decreased Bax expression; non-amyloidogenic APP shedding; and increased neurite outgrowth in neuronal cells. Animal studies investigating the influence of P2Y receptors in middle cerebral artery occlusion (MCAO) models for stroke prove beneficial effects of P2Y receptor antagonists. In MCAO mice and rats, the application of broad-range P2 receptor antagonists decreased the infarct volume and improved neurological outcome. Moreover, antagonists of the P2Y 1 receptor, one of the most abundant P2Y receptor subtypes in brain tissue, decreased neuronal loss and improved spatial memory in rats after traumatic brain injury (TBI). Currently available data show a discrepancy between in vitro and in vivo models concerning the benefits of P2Y receptor activation in pathological conditions. In vitro models demonstrate protection by P2Y receptor agonists, but in vivo P2Y receptor activation deteriorates the outcome after MCAO and controlled cortical impact brain injury, a TBI model. To broaden the scope of the review, we additionally discuss publications that demonstrate detrimental effects of P2Y receptor agonists in vitro and publications showing protective effects of agonists in vivo. All these studies help to better understand the significant role of P2Y receptors especially in stroke models and to develop pharmacological strategies for the treatment of stroke.

Neurogenic Differentiation of Mesenchymal Stem Cells Induces Alterations in Extracellular Nucleotides Metabolism

“…Effective ADP metabolism on both types of cells may also be realized through ecto‐adenylate kinase activity and/or exo‐nucleotidases specific for diphosphonucleotides (NTPDase5 and 6). ADP and its receptors are often linked with trophic effects of nucleotide signaling [Espada et al, ; Wei et al, ; Förster and Reiser, ], thus the precise control of extracellular ADP concentration through enzymatic activity is essential for both hUC‐MSCs and neurogenically induced hUC‐MSCs. Surprisingly, the enzymatic extracellular AMP hydrolysis and extracellular adenosine production is more effective after hUC‐MSCs transdifferentiation, that is in contrast to the expression level of CD73 gene.…”

Update of P2Y receptor pharmacology: IUPHAR Review 27

“…Microglial P2Y 12 receptors respond to ADP as a “find me” signal and induces activation and chemotaxis, suggesting a role of this receptor in neurodegeneration and pain signalling (Förster & Reiser, 2015; Tozaki‐Saitoh et al, 2008). Platelets, which express P2Y 1 and P2Y 12 receptors, themselves play an important role not only in thrombosis but also in modulating inflammatory responses through release of inflammatory mediators or compounds with trophic activity and exposure of P‐selectin, CD40, and CD40 ligand.…”

Expression and function of the metabotropic purinergic P2Y receptor family in experimental seizure models and patients with drug‐refractory epilepsy

“…P2Y 12‐14 are coupled to Gi proteins, inhibiting adenylate cyclase and decreasing cAMP production . P2Y signaling is involved in numerous physiologic processes, including neurotransmission, neurogenesis, and glial cell communication, and causal effects of P2Y signaling on disease pathology have been reported for both acute insults to the brain, such as stroke and traumatic brain injury and chronic brain diseases such as Alzheimer's disease …”