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Adenosine receptor signaling: a key to opening the blood-brain door.

Bynoe MS, Viret C, Yan A, Kim DG - Fluids Barriers CNS (2015)

Bottom Line: In line with this hypothesis, induction of AR signaling by selective agonists efficiently augments BBB permeability in a transient manner and promotes the entry of macromolecules into the CNS.Conversely, antagonism of AR signaling blocks the entry of inflammatory cells and soluble factors into the brain.Thus, AR modulation of the BBB appears as a system susceptible to tighten as well as to permeabilize the BBB.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 1853, USA. msb76@cornell.edu.

ABSTRACT
The aim of this review is to outline evidence that adenosine receptor (AR) activation can modulate blood-brain barrier (BBB) permeability and the implications for disease states and drug delivery. Barriers of the central nervous system (CNS) constitute a protective and regulatory interface between the CNS and the rest of the organism. Such barriers allow for the maintenance of the homeostasis of the CNS milieu. Among them, the BBB is a highly efficient permeability barrier that separates the brain micro-environment from the circulating blood. It is made up of tight junction-connected endothelial cells with specialized transporters to selectively control the passage of nutrients required for neural homeostasis and function, while preventing the entry of neurotoxic factors. The identification of cellular and molecular mechanisms involved in the development and function of CNS barriers is required for a better understanding of CNS homeostasis in both physiological and pathological settings. It has long been recognized that the endogenous purine nucleoside adenosine is a potent modulator of a large number of neurological functions. More recently, experimental studies conducted with human/mouse brain primary endothelial cells as well as with mouse models, indicate that adenosine markedly regulates BBB permeability. Extracellular adenosine, which is efficiently generated through the catabolism of ATP via the CD39/CD73 ecto-nucleotidase axis, promotes BBB permeability by signaling through A1 and A2A ARs expressed on BBB cells. In line with this hypothesis, induction of AR signaling by selective agonists efficiently augments BBB permeability in a transient manner and promotes the entry of macromolecules into the CNS. Conversely, antagonism of AR signaling blocks the entry of inflammatory cells and soluble factors into the brain. Thus, AR modulation of the BBB appears as a system susceptible to tighten as well as to permeabilize the BBB. Collectively, these findings point to AR manipulation as a pertinent avenue of research for novel strategies aiming at efficiently delivering therapeutic drugs/cells into the CNS, or at restricting the entry of inflammatory immune cells into the brain in some diseases such as multiple sclerosis.

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Related in: MedlinePlus

Cells of the central nervous system (CNS) not only produce adenosine but are also regulated by adenosine. Cells of the CNS, such as astrocytes, microglia, pericytes and neuronal cells can produce adenosine or their activity/function is regulated by adenosine. Adenosine regulates the blood brain barrier permeability and is involved in neural transmission and glial cell immune function and metabolism
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Fig3: Cells of the central nervous system (CNS) not only produce adenosine but are also regulated by adenosine. Cells of the CNS, such as astrocytes, microglia, pericytes and neuronal cells can produce adenosine or their activity/function is regulated by adenosine. Adenosine regulates the blood brain barrier permeability and is involved in neural transmission and glial cell immune function and metabolism

Mentions: Adenosine is a purine nucleoside involved in a myriad host functions. It is a potent immune regulator and, in addition, is notable for its role in regulating inflammation, wound healing, angiogenesis and myocardial contractility (Fig. 2). Within the CNS, adenosine is released by both neurons and glial cells. It regulates multiple physiological functions such as sleep, arousal, neuroprotection, learning and memory, cerebral blood circulation as well as pathological phenomena such as epilepsy. These effects involve adenosine modulation of neuronal excitability, vasodilatation, release of neurotransmitters, synaptic plasticity/function and local inflammatory processes [15–17] (Fig. 3).Fig. 2


Adenosine receptor signaling: a key to opening the blood-brain door.

Bynoe MS, Viret C, Yan A, Kim DG - Fluids Barriers CNS (2015)

Cells of the central nervous system (CNS) not only produce adenosine but are also regulated by adenosine. Cells of the CNS, such as astrocytes, microglia, pericytes and neuronal cells can produce adenosine or their activity/function is regulated by adenosine. Adenosine regulates the blood brain barrier permeability and is involved in neural transmission and glial cell immune function and metabolism
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4557218&req=5

Fig3: Cells of the central nervous system (CNS) not only produce adenosine but are also regulated by adenosine. Cells of the CNS, such as astrocytes, microglia, pericytes and neuronal cells can produce adenosine or their activity/function is regulated by adenosine. Adenosine regulates the blood brain barrier permeability and is involved in neural transmission and glial cell immune function and metabolism
Mentions: Adenosine is a purine nucleoside involved in a myriad host functions. It is a potent immune regulator and, in addition, is notable for its role in regulating inflammation, wound healing, angiogenesis and myocardial contractility (Fig. 2). Within the CNS, adenosine is released by both neurons and glial cells. It regulates multiple physiological functions such as sleep, arousal, neuroprotection, learning and memory, cerebral blood circulation as well as pathological phenomena such as epilepsy. These effects involve adenosine modulation of neuronal excitability, vasodilatation, release of neurotransmitters, synaptic plasticity/function and local inflammatory processes [15–17] (Fig. 3).Fig. 2

Bottom Line: In line with this hypothesis, induction of AR signaling by selective agonists efficiently augments BBB permeability in a transient manner and promotes the entry of macromolecules into the CNS.Conversely, antagonism of AR signaling blocks the entry of inflammatory cells and soluble factors into the brain.Thus, AR modulation of the BBB appears as a system susceptible to tighten as well as to permeabilize the BBB.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 1853, USA. msb76@cornell.edu.

ABSTRACT
The aim of this review is to outline evidence that adenosine receptor (AR) activation can modulate blood-brain barrier (BBB) permeability and the implications for disease states and drug delivery. Barriers of the central nervous system (CNS) constitute a protective and regulatory interface between the CNS and the rest of the organism. Such barriers allow for the maintenance of the homeostasis of the CNS milieu. Among them, the BBB is a highly efficient permeability barrier that separates the brain micro-environment from the circulating blood. It is made up of tight junction-connected endothelial cells with specialized transporters to selectively control the passage of nutrients required for neural homeostasis and function, while preventing the entry of neurotoxic factors. The identification of cellular and molecular mechanisms involved in the development and function of CNS barriers is required for a better understanding of CNS homeostasis in both physiological and pathological settings. It has long been recognized that the endogenous purine nucleoside adenosine is a potent modulator of a large number of neurological functions. More recently, experimental studies conducted with human/mouse brain primary endothelial cells as well as with mouse models, indicate that adenosine markedly regulates BBB permeability. Extracellular adenosine, which is efficiently generated through the catabolism of ATP via the CD39/CD73 ecto-nucleotidase axis, promotes BBB permeability by signaling through A1 and A2A ARs expressed on BBB cells. In line with this hypothesis, induction of AR signaling by selective agonists efficiently augments BBB permeability in a transient manner and promotes the entry of macromolecules into the CNS. Conversely, antagonism of AR signaling blocks the entry of inflammatory cells and soluble factors into the brain. Thus, AR modulation of the BBB appears as a system susceptible to tighten as well as to permeabilize the BBB. Collectively, these findings point to AR manipulation as a pertinent avenue of research for novel strategies aiming at efficiently delivering therapeutic drugs/cells into the CNS, or at restricting the entry of inflammatory immune cells into the brain in some diseases such as multiple sclerosis.

Show MeSH
Related in: MedlinePlus