negative regulation of blood-brain barrier permeability

Definition

Target type: biologicalprocess

Any process that decreases blood-brain barrier permeability, the quality of the blood-brain barrier that allows for a controlled passage of substances (e.g. macromolecules, small molecules, ions) into and out of the brain. [GO_REF:0000058, GOC:als, GOC:aruk, GOC:bc, GOC:TermGenie, PMID:22524708, PMID:30280653]

The blood-brain barrier (BBB) is a highly specialized and tightly regulated interface between the blood and the brain, ensuring the proper functioning of the central nervous system. Negative regulation of BBB permeability refers to the processes that restrict the movement of molecules, cells, and other substances from the blood into the brain parenchyma. This intricate process is critical for maintaining brain homeostasis, protecting the brain from pathogens and toxins, and preventing neuroinflammation.

Here are some key mechanisms involved in negative regulation of BBB permeability:

1. **Tight Junctions:** The BBB is characterized by the presence of tight junctions, specialized cell-cell junctions that seal the gaps between endothelial cells. These junctions are formed by transmembrane proteins, including claudins, occludins, and junctional adhesion molecules (JAMs), which interact with their counterparts on adjacent cells. The tight junctions restrict the paracellular pathway, which is the movement of substances through the spaces between cells.

2. **Efflux Transporters:** The BBB expresses a variety of efflux transporters, such as P-glycoprotein (P-gp), multidrug resistance protein 1 (MDR1), and breast cancer resistance protein (BCRP). These transporters actively pump drugs, toxins, and other potentially harmful substances out of the brain parenchyma back into the bloodstream, preventing their accumulation within the brain.

3. **Enzymes:** The BBB expresses enzymes that can degrade or inactivate certain substances before they can enter the brain. For example, monoamine oxidase (MAO) degrades neurotransmitters, while glucuronyl transferases conjugate drugs and toxins, rendering them less permeable.

4. **Metabolic Barriers:** Some substances may not be able to cross the BBB because they are not metabolized in the brain. For instance, the brain lacks the enzymes necessary to break down certain drugs, preventing their entry.

5. **Endothelial Cell Cytoskeleton:** The cytoskeleton of endothelial cells, composed of actin and microtubules, provides structural integrity and regulates the formation and permeability of tight junctions.

6. **Pericytes and Astrocytes:** Pericytes and astrocytes, cells that surround brain capillaries, contribute to the negative regulation of BBB permeability. Pericytes can contract and regulate blood flow, while astrocytes provide structural support, release signaling molecules, and participate in the formation of the glia limitans, a barrier between astrocytes and neurons.

7. **Immune Regulation:** The BBB also plays a critical role in immune surveillance and protection. It prevents immune cells from entering the brain parenchyma, but it can also allow for the entry of specific immune cells in response to infection or inflammation. The BBB can modulate the immune response in the brain by controlling the movement of immune cells, cytokines, and chemokines.

Negative regulation of BBB permeability is a complex process that involves multiple interacting mechanisms. It is a dynamic and responsive system that can be modulated by a variety of factors, including disease states, drugs, and environmental exposures. Understanding the molecular mechanisms underlying BBB permeability is crucial for developing targeted therapies for a variety of neurological diseases.'
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