Modulation of Blood–Brain Barrier Permeability by Activating Adenosine A2 Receptors in Oncological Treatment

Abstract

The blood–brain barrier (BBB) plays an important protective role in the central nervous system and maintains its homeostasis. It regulates transport into brain tissue and protects neurons against the toxic effects of substances circulating in the blood. However, in the case of neurological diseases or primary brain tumors, i.e., gliomas, the higher permeability of the blood-derived substances in the brain tissue is necessary. Currently applied methods of treatment for the primary brain neoplasms include surgical removal of the tumor, radiation therapy, and chemotherapy. Despite the abovementioned treatment methods, the prognosis of primary brain tumors remains bad. Moreover, chemotherapy options seem to be limited due to low drug penetration into the cancerous tissue. Modulation of the blood–brain barrier permeability may contribute to an increase in the concentration of the drug in the CNS and thus increase the effectiveness of therapy. Interestingly, endothelial cells in cerebral vessels are characterized by the presence of adenosine 2A receptors (A2AR). It has been shown that substances affecting these receptors regulate the permeability of the BBB. The mechanism of increasing the BBB permeability by A2AR agonists is the actin-cytoskeletal reorganization and acting on the tight junctions. In this case, the A2AR seems to be a promising therapy target. This article aims to assess the possibility of increasing the BBB permeability through A2AR agonists to increase the effectiveness of chemotherapy and to improve the results of cancer therapy.

Nanoparticles for efficient drug delivery and drug resistance in glioma: New perspectives

“…In addition, the cytoskeleton, consisting of actin microfilaments, microtubules, and intermediate fibers, is involved in maintaining the integrity of endothelial intercellular junctions. The actin microfilament system is specifically associated with various membrane adhesion proteins such as calreticulin, occludin, protein complexes, and functional intercellular proteins, and its structure is closely related to the endothelial cell tension formed by the phosphorylation of myosin light chains and actin stress fibers 36,37 . Microtubules are involved in the rapid self‐organization of actin microfilaments and focal adhesions, isometric cell contraction, and facilitation of leukocyte migration across the endothelium.…”

“…The actin microfilament system is specifically associated with various membrane adhesion proteins such as calreticulin, occludin, protein complexes, and functional intercellular proteins, and its structure is closely related to the endothelial cell tension formed by the phosphorylation of myosin light chains and actin stress fibers. 36 , 37 Microtubules are involved in the rapid self‐organization of actin microfilaments and focal adhesions, isometric cell contraction, and facilitation of leukocyte migration across the endothelium. Intermediate fibers are dynamically altered during reorganization of actin microfilaments and microtubules, but their specific mechanisms of action in cytoskeletal changes are still unknown.…”

Delivering Therapeutics to Glioblastoma: Overcoming Biological Constraints

“…All these methods downregulate the expression of tight junction proteins. FUS is also involved in increasing transcytosis [22,30].…”

Current Strategies to Enhance Delivery of Drugs across the Blood–Brain Barrier

“…Another essential role of A2A receptor agonists is to prevent tissue from injury during ischemia-reperfusion, such as in hemorrhagic shock, by lowering inflammation (affecting neutrophils, platelets, macrophages, and T cells) [ 132 , 133 ]. Furthermore, adenosine agonists in the central nervous system (CNS) reduce inflammation and protect nerve cells [ 134 ].…”