Blood Brain Barrier - Methods For Analyzing Drug Permeability Through It
Because of the human body's blood-brain barrier, medicinal chemicals cannot be delivered into the brain to treat different neurological illnesses successfully.
Various in silico, in vitro, and in vivo approaches may be used to examine the potential of such drugs penetrating the blood brain barrier.
Some often provide inconsistent findings, while others are not practical in a high-throughput screening setting.
The blood–brain barrier (BBB) is a highly selective semipermeable border of endothelial cells that prevents circulating blood solutes from passing non-selectively into the extracellular fluid of the central nervous system, where neurons dwell.
COPYRIGHT_OAPL: Published on https://www.oapublishinglondon.com/pop/blood-brain-barrier/ by Dr. Cooney Blades on 2022-06-09T05:40:51.009Z
Endothelial cells of the capillary wall, astrocyte end-feet ensheathing the capillary, and pericytes embedded in the capillary basement membrane create the blood brain barrier.
This system provides for the passive diffusion of certain small molecules as well as the selective and active transport of nutrients, ions, organic anions, and macromolecules such as glucose and amino acids that are essential for brain function.
The blood–brain barrier prevents viruses from entering the brain, as well as big or hydrophilic molecules from entering the cerebrospinal fluid while enabling hydrophobic molecules (O2, CO2, hormones) and tiny non-polar molecules to pass through.
Using particular transport proteins, barrier cells actively transfer metabolic products such as glucose over the barrier.
The barrier also prevents the entry of peripheral immunological components into the CNS, such as signaling molecules, antibodies, and immune cells, therefore protecting the brain from harm caused by peripheral immune events.
Because of their speed, versatility, and cheap cost, in silico prediction approaches have favored blood brain barrier research during the past several decades.
A typical high-throughput screening (HTS) approach filters and identifies CNS active drug/hit/lead-like compounds using either a descriptor or a molecular docking-based strategy.
There were several false-positive results due to the simple addition of molecular characteristics (molecular weight, the sum of nitrogen and oxygen atoms, etc.) without considering blood brain barrier transport modes, such as multidrug P-glycoprotein (P-GP) transporter efflux.
To provide direct access to the brain endothelium without hindrance from other brain structures, cells of both cerebral and non-cerebral origin are employed as in vitro models of the blood brain barrier.
Brain capillary isolation and cultivation of brain capillary endothelial cells (BCECs) are both used.
Because of the limitations of the presently available immortalized BCEC lines, some of them may be exploited to construct a barrier for drug-like candidates.
BCECs may be co-cultured with astrocytes, C6 glioma cells, or pericytes to increase barrier qualities.
In a Transwell culture method, these cells may be cultured with or without interaction with BCECs.
To investigate blood brain barrier permeability, transwell models have been built.
Hollow fibers that simulate capillaries and enable co-culture of various cell types were employed in these models.
The first blood brain barrier model to use this technology was bovine aortic endothelial cells co-cultured with glial cells.
Recently, immortalized swine brain endothelial cells have been employed.
This approach indicated that hCMEC/D3 cells cultivated in pulsatile flow settings retain physiological permeability barrier characteristics in vitro.
Drug concentrations in the brain and blood are measured following intravenous drug administration.
Under proper physiological and pathological settings, these invasive procedures can determine the logBB and logPS (logarithm of permeability–surface area product) values.
Brain homogenates are analyzed using high-performance liquid chromatography (HPLC), in situ brain perfusion, and intracerebral microdialysis.
In situ brain perfusion does not affect blood-brain barrier integrity and may be utilized to calculate solute permeability coefficients correctly.
The rat is the most often used species for cerebral perfusion investigations, while this approach has also been utilized effectively in the dog, guinea pig, and mouse studies.
This technology enables monitoring drug concentrations in the brain over time within the same animal and the probing of multiple brain regions as potential therapeutic targets.
It is composed of capillary endothelial cells and basement membrane, neuroglial membrane, and glial podocytes, which are astrocyte projections.
These three components act in tandem to restrict the entrance of different substances into the cerebral blood flow and, ultimately, the brain parenchyma.
A network of blood arteries and tissue made up of closely spaced cells that aids in the prevention of hazardous chemicals reaching the brain.
Some substances, including as water, oxygen, carbon dioxide, and general anesthetics, may pass through the blood-brain barrier and enter the brain.
Vascular variables (stroke, hypertension, diabetes, and so on) and genetic factors (such as APOE4) induce vascular system deficiencies, which lead to blood brain barrier impairment and oligemia (lower cerebral blood flow), which then correlate with dementia and neuronal degeneration.
In the past several decades, business and academia have developed many in silico, in vitro, and in vivo methodologies for estimating drug-like compounds transported across the blood brain barrier for pharmaceutical research.
These strategies are now highlighted in this evaluation for their inherent benefits and drawbacks.
The more trustworthy in vivo approaches are nevertheless inapplicable for high-throughput screening of massive molecular databases created by combinatorial chemical operations.
Bioscientists extensively used new in silico and in vitro approaches to accelerate compound selection, thoroughly analyze brain absorption for chemical entities, and better comprehend the complicated processes behind blood brain barrier transport.
As a result, using a combined screening procedure that includes in silico, in vitro, and in vivo methodologies may provide higher reliabilities in predicting and evaluating the blood brain barrier penetration capability of prospective drug candidates in people.