Abstract
Purinergic P2X receptors, when activated under pathological conditions, participate in induction of the inflammatory response and/or cell death. Both neuroinflammation and neurodegeneration represent hallmarks of multiple sclerosis (MS), an autoimmune disease of the central nervous system. In the current study, we examined whether P2X7R is expressed in brain microvasculature of rats subjected to experimental autoimmune encephalomyelitis (EAE) and explore possible relationships with blood-brain barrier (BBB) protein—claudin-5 after administration of P2X7R antagonist—Brilliant Blue G (BBG). Capillary fraction isolated from control and EAE rat brains was subjected to immunohistochemical and Western blot analyses. We document the presence of P2X7R in brain capillaries isolated from brain tissue of EAE rats. P2X7R is found to be localized on the abluminal surface of the microvessels and is co-expressed with PDGFβR, a marker of pericytes. We also show over-expression of this receptor in isolated capillaries during the course of EAE, which is temporally correlated with a lower protein level of PDGFβR, as well as claudin-5, a tight junction-building protein. Administration of a P2X7R antagonist to the immunized rats significantly reduced clinical signs of EAE and enhances protein expression of both claudin-5 and PDGFβR. These results indicate that P2X7 receptor located on pericytes may contribute to pathological mechanisms operated during EAE in cerebral microvessels influencing the BBB integrity.
Highlights
During neuroinflammation, activated or injured cells release high levels of extracellular ATP which act via specific metabotropic (P2Y) or ionotropic (P2X) groups of receptors
Claudin-5-positive endothelial cells were found to form a deeper layer of the vessel, whereas P2X7 receptor (P2X7R)-positive cells were observed on the abluminal surface of microvessels
To confirm that P2X7R is localized on pericytes, these cells were contacted with an antibody against platelet derived growth factor β receptor (PDGFβR), which is a specific marker of pericytes
Summary
During neuroinflammation, activated or injured cells release high levels of extracellular ATP which act via specific metabotropic (P2Y) or ionotropic (P2X) groups of receptors. Apart from a release of inflammatory mediators, over-activation of this receptor may produce a release of excitatory neurotransmitters such as glutamate [4]. This type of purinergic receptor evokes significant interest in context of inflammatory/neurodegenerative changes observed in various CNS disorders [6], including multiple sclerosis (MS) [7,8,9]. MS is an autoimmune neuroinflammatory disease which leads to progressive physical and cognitive disability It is characterized by inflamed plaques of demyelination in the white matter, oligodendroglial cell death, and damage of axons. Studies performed on an animal model of MS suggest the existence of a strong correlation between BBB dysfunction and the severity of the disease [11, 12]
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