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

Author:

Fernandez Mercedes1ORCID,Nigro Manuela1,Travagli Alessia1,Pasquini Silvia2ORCID,Vincenzi Fabrizio1ORCID,Varani Katia1ORCID,Borea Pier Andrea3,Merighi Stefania1ORCID,Gessi Stefania1

Affiliation:

1. Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy

2. Department of Chemical, Pharmaceutical and Agricultural Science, University of Ferrara, 44121 Ferrara, Italy

3. University of Ferrara, 44121 Ferrara, Italy

Abstract

The blood–brain barrier (BBB) is a biological barrier that protects the central nervous system (CNS) by ensuring an appropriate microenvironment. Brain microvascular endothelial cells (ECs) control the passage of molecules from blood to brain tissue and regulate their concentration-versus-time profiles to guarantee proper neuronal activity, angiogenesis and neurogenesis, as well as to prevent the entry of immune cells into the brain. However, the BBB also restricts the penetration of drugs, thus presenting a challenge in the development of therapeutics for CNS diseases. On the other hand, adenosine, an endogenous purine-based nucleoside that is expressed in most body tissues, regulates different body functions by acting through its G-protein-coupled receptors (A1, A2A, A2B and A3). Adenosine receptors (ARs) are thus considered potential drug targets for treating different metabolic, inflammatory and neurological diseases. In the CNS, A1 and A2A are expressed by astrocytes, oligodendrocytes, neurons, immune cells and ECs. Moreover, adenosine, by acting locally through its receptors A1 and/or A2A, may modulate BBB permeability, and this effect is potentiated when both receptors are simultaneously activated. This review showcases in vivo and in vitro evidence supporting AR signaling as a candidate for modifying endothelial barrier permeability in the treatment of CNS disorders.

Funder

#NEXTGENERATIONEU

Ministry of University and Research

Project MNESYS

Publisher

MDPI AG

Subject

Pharmaceutical Science

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