Crossing The Blood Brain Barrier Biology Essay

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The Blood Brain Barrier protects neurones from toxic substances in blood, as it allows the exchange of nutrients and waste products between neurones and blood. Once the solute traverses the blood brain barrier, instantaneous drug or solute equilibrium throughout brain interstitial fluid is achieved. The surface area of the BBB is approximately 20 m2 and consists of capillaries, which are formed endothelial cells connected by tight junctions with the absence of fenestrations. The blood barrier prevents brain uptake of less than 98% of all potential neuro-therapeutics. [1] The endothelial cells of the capillaries in the Blood Brain Barrier are different to capillaries in other tissues. As stated previously the endothelial cells of the BBB contain tight junctions, therefore para-cellular pathways does not occur, but trans-cellular pathways such as direct transfer of small molecules across plasma membrane through passive diffusion or catalysed transport occurs. [2]

The formation of novel drugs for the brain has not been achieved rapidly with molecular neurosciences; this is due to the blood brain barrier. The penetration of large molecules across the BBB does not occur; this is same for most small molecule drugs. Most drugs that have been discovered, do not have correct properties to penetrate the BBB. This impermeability of BBB is due to numerous transport systems which are situated on the luminal and abluminal membranes. These mediate the transport in either brain - to - blood or blood - to - brain direction. The transport systems involved in the BBB are the Carrier Mediated Transport (CMT), active efflux transport (AET), and receptor mediated transported (RMT). The CMT systems are expressed on both luminal and abluminal membranes, [3] This system causes small polar nutrients between blood and brain to pass through. Examples of small polar molecules are glucose, amino acids, choline, purine nucleobases and nucleosides etc. The system catalyses the transfer of molecules and this occurs through stereospecific transporter proteins. Examples of CMT systems are outlines below:

GLUT-1 (Glucose Transporters)

LAT 1 (Large Neutral amino acid transporters)

MCT1 (Lactate transporters) [2]

For particular large molecules such as Transferrin, Leptin and Insulin, which are endogenous neuropeptides, penetrate the BBB through Receptor Mediated Transport systems (RMT). Particular ligand specific receptor systems are used, for the mediation of RMT system. Insulin Receptor and Transferin receptors or other RMT systems can either by selectively localised to the luminal membrane (blood) or abluminal membrane (brain) or on both membranes [3]. Large, biologically active proteins can be delivered to the brain by exploiting RMT. The delivery of proteins is achieved by chemically linking the protein to an antibody raised against a receptor, creating chimeric conjugate. On binding to receptor, the chimeric conjugate is taken up into the endothelial cell. Once this occurs transportation occurs through the BBB and into the blood, dissociation of the protein and the antibody occur and the protein is released. [2]

Finally the active efflux system mediates unidirectional efflux from brain-to-blood. One particular type of AET system discovered at the BBB is the the P-glycoprotein (Pgp), which is the prototypic. But there are several AETs other than the P-glycoprotein that cause the exportation of certain molecules from the brain back into the blood. Examples of AET systems in the brain are:

P-gp (P glycoprotein)

Mrds (multidrug resistance)

MRPS (multidrug resistance-associated proteins)

OATs (organic anion transporters) : which pump molecules and solutes back out the brain

MCT (monocarboxylic acid transporter) : which pump molecules and solutes back out the brain

As there are three isoforms of mdrs (multidrug resistance) in the rat (mdrla, mdrlb, and mdr2) and two isoforms of mdr1 and mdr2 in humans. It was shown that mdr1a implicated in the efflux of drugs form the CNS, which localised to capillary endothelial cells. Iain Martin showed that when a mrda1 knockout mice was produced there was an increase in the BBB penetration for wide range of drugs, for example loperamide, dexamethasone, morphine, vinblastine, saquinavir etc).[4] Likewise if the PGP is knocked out, the efflux mechanisms do not occur and therefore allows the drug to pass the BBB. For a drug to pass through the BBB, it has to be in the form of a substrate for the AET systems. The properties that the p-glycoproteins substrates should contain for the drug penetrating the BBB should be lipophilic, planar ring system, molecular weight less than 400 and positive charge at ph 7.4. [2] As AET systems aim in efflux molecules back out of the brain and into the blood, therefore researchers have to find a solution of overcoming this problem.

Most drugs penetrate the BBB by passive diffusion, lipophilicity, charge, hydrogen bonding and size are important physicochemical properties ( lipinski's rule). [2] Therefore there are many properties of drug that prevent it from passing the BBB. One property has linear correlation between the brain penetration and dynamic polar surface area (A2). [5] Polar Surface area is surface areas (A2) occupied by N and O atoms, and polar Hydrogens bonded to these hetroatoms. Therefore hydrogen bonding was deemed to be the key descriptor and polar surface area is an easily assessable descriptor for H-Bonding. [2] In kelder et al (1999) it was stated that brain penetration decreases with increasing polar surface area, as drug molecules were studied for brain penetration. The polar surface area was calculated and correlated with brain penetration data. In this study 776 CNS and 15690 Non- CNS drugs were orally administered that had reached Phase II studies. There was clear distribution of CNS and non-CNS drugs. [5] In another study, the examination of the relationship between the logarithm of brain/blood concentration ratios at steady state conditions with polar molecular surface area. It was discovered that brain penetration increases with increase in hydrophobicity. Therefore brain pen can be improved by lowering PSA but this also tended to decrese solubility. So a balance in properties was needed. [6] It can be noted in Norinder et al (2002), the models for prediction of distribution of drugs into the brain using computed parameters.[7]

In order to assess if the drug has penetrated the BBB, is by measuring drug concentrations at the CSF. A number of studies suggest that drug concentrations in bECF provide the most relevant link with pharmacological action, as brain levels correlated well with CSF level, as both are at steady state and in equilibrium.[2] The CSF is known as the cerebrospinal fluid, which is particularly originated in the cranial sub-arachnoid space, four ventricles and spnal sub-arachnoid space. In order to measure the CSF drug concentration, in vivo studies of the rat brain should be used. In Friden et al (2009) the estimation of the steady state unbound brain-to-plasma concentration ratio Kp,uu,brain (Cu,brainISF/Cu,p) in rats was determined. The Cu,brainISF and Cu,p stands for the difference between the concentration of the unbound drug in the brain interstitial fluid and in the plasma respectively. It was discovered that if Kp,uu,brain drug efflux and influx can occur if it is less than or greater than 1 respectively. Friden et al (2009) also stated that lower the value of Kp,uu,brain, the greater the advantage of the drug acting therapeutic with possible CNS side effects.[8] As many lipophilic drugs enter the brain but do not act on the target protein. Therefore it much easier to measure the free (unbound) drug concentrations or use a receptor occupancy. This was shown in study by waterbeemde et al (2001), the receptor occupancy was calculated from the free (unbound) concentration of drug in plasma, the concentration of CSF compared to that measured by PET scan for sulpride. Therefore drug concentration in CSF is a good indicator of free drug available for interaction with receptor in the brain. [9] The increase use of PET imaging enables to accurately measure the BBB penetration and target protein occupancy for particular CNS drugs. To obtain no unbound drug we can change the pharmacokinetic properties of the drug to improve BBB penetration. Therefore to treat CNS diseases the drug has to have small molecular size, is reasonably lipophilic, is relatively a weak ligand of an efflux pump, has a decrease level of plasma protein binding, and has a volume of distribution approximately 1 liter/kg. [10] In order for the a drug to pass the BBB, the Monika set of parameters are consistent with this, which are outlined below:

MW <450

PSA<60-70 A2



Rot Bond<9

Log P = 0 to 6

Log D = -1 to 5

Therefore in order for a drug to pass through the Blood Brain Barrier a balance of properties is needed.