Purinergic signaling: A gatekeeper of blood-brain barrier permeation

Abstract

This review outlined evidence that purinergic signaling is involved in the modulation of blood-brain barrier (BBB) permeability. The functional and structural integrity of the BBB is critical for maintaining the homeostasis of the brain microenvironment. BBB integrity is maintained primarily by endothelial cells and basement membrane but also be regulated by pericytes, neurons, astrocytes, microglia and oligodendrocytes. In this review, we summarized the purinergic receptors and nucleotidases expressed on BBB cells and focused on the regulation of BBB permeability by purinergic signaling. The permeability of BBB is regulated by a series of purinergic receptors classified as P2Y1, P2Y4, P2Y12, P2X4, P2X7, A1, A2A, A2B, and A3, which serve as targets for endogenous ATP, ADP, or adenosine. P2Y1 and P2Y4 antagonists could attenuate BBB damage. In contrast, P2Y12-mediated chemotaxis of microglial cell processes is necessary for rapid closure of the BBB after BBB breakdown. Antagonists of P2X4 and P2X7 inhibit the activation of these receptors, reduce the release of interleukin-1 beta (IL-1β), and promote the function of BBB closure. In addition, the CD39/CD73 nucleotidase axis participates in extracellular adenosine metabolism and promotes BBB permeability through A1 and A2A on BBB cells. Furthermore, A2B and A3 receptor agonists protect BBB integrity. Thus, the regulation of the BBB by purinergic signaling is complex and affects the opening and closing of the BBB through different pathways. Appropriate selective agonists/antagonists of purinergic receptors and corresponding enzyme inhibitors could modulate the permeability of the BBB, effectively delivering therapeutic drugs/cells to the central nervous system (CNS) or limiting the entry of inflammatory immune cells into the brain and re-establishing CNS homeostasis.

The complex role of the chemokine CX3CL1/Fractalkine in major depressive disorder: A narrative review of preclinical and clinical studies

“…Although there is evidence for FKN involvement in the regulation of BBB permeability, it is unclear whether peripheral FKN can directly cross the BBB into the CNS and vice versa ( Wang et al, 2023 ). There has been some suggestion of BBB-hyperpermeability in the context of MDD ( Medina-Rodriguez and Beurel, 2022 ) which may increase the likelihood of permeability to chemokines like FKN.…”

Update on the mechanism of microglia involvement in post-stroke cognitive impairment

“…Some scholars believe that they may cause side effects related to cognitive function because they involve the P2Y12 receptor (Xu et al, 2016;Wang et al, 2023). In fact, there is evidence that the P2Y12 receptor may enter the brain and play a potential role due to the destruction of the BBB (Li et al, 2020;Wang et al, 2023).…”

Strategies for Drug Delivery into the Brain: A Review on Adenosine Receptors Modulation for Central Nervous System Diseases Therapy

“…Adenosine is an endogenous purine nucleoside that, under physiological conditions, is mainly generated inside cells from the substrate S-Adenosyl-L-homocysteine through the catalytic action of the enzyme S-Adenosyl-L-homocysteine hydrolase, leading to adenosine and homocysteine as the products. Adenosine is a basic constituent of nucleic acids and can also be present in the forms of AMP, ADP and ATP; these purine molecules play a crucial role in cellular energy supply and in the transfer of information within and across cells [20,62,63].…”

“…A1Rs and A2ARs are expressed by ECs, neurons, glial cells and immune cells [62,76]. Since ECs also express CD73, it is hypothesized that these cells are sensitive to the potential damage induced by extracellular ATP, which is known to be an injury signal in the brain [77,78], and might convert ATP into adenosine via the action of the ectoenzyme CD73.…”