The Blood-Brain Barrier
The brain is the epicentre of an eclectic array of physiological activity. It integrates information from the external environment with signals from the internal environment in order to execute specific activities. With all the special activities that occur at the neuronal level, it is paramount that the chemical environment in which these cells operate is strictly regulated. This is the primary function of the blood-brain barrier. This selectively permeable membrane regulates the passage of a multitude of large and small molecules into the microenvironment of the neurons. It achieves this feat by with the aid of multiple cellular transport channels scattered along the membrane. These include amino acid transporters, glucose transporter 1 (GLUT1), nucleouside & nucleotide transporters, monocarboxylate transporters (MCT1 and MCT2) and other ion transporters (Na+/K+-ATPase pumps) that facilitate the transport of essential molecules into the brain.
In addition to facilitating the uptake of amino acids, the amino acid transporters may inadvertently transport undesirable heavy metals into the brain’s immediate environment. Consequently, at high enough concentrations, this will result in neurotoxicity. GLUT1 and the MCT transporters carry glucose, and lactate and ketones, respectively.
This article will look at the overall structure of the blood-brain, blood-nerve, and blood-cerebrospinal fluid barriers found throughout the nervous system. Additionally, special attention will be paid to those areas within the brain that lack a blood-brain barrier and to clinically relevant points with respect to this membrane.
The brain has a large network of arterial and venous vessels taking blood to and from (respectively) brain tissue. However, most of the action occurs at the level of the capillaries. Both the luminal and abluminal (outer surface of the vessel) sides are lined by key structures that contribute to the integrity of the cells. Firstly, squamous epithelial cells form the endothelial wall of the capillaries; the luminal surface of these cells comes into contact with circulating blood and its constituents. The abluminal surface is in contact with a circumferentially continuous basement membrane.
The endothelial cells are anchored to each other by zonula occludens or tight junctions, as well as zonulae adherens. The former provide structural support to the endothelial wall, while the latter physically connects adjacent cells. Additionally, the tight junctions circumscribe the cells and provide a seal with all adjacent cells. Therefore, the endothelium functions as an impermeable barrier between the capillary lumen and brain tissue.
Studies conducted on other mammals have implicated pericytes as integral components in the formation of the blood-brain barrier. These cells encircle endothelial cells of capillaries and are able to contract in order to regulate capillary blood flow. Consequently, the contractility also regulates the amount of blood flowing through the capillaries, thus enhancing the blood-brain barrier. Furthermore, some theories suggest that pericytes not only promote the formation of tight junctions, but they also inhibit the production of chemicals that promote vascular permeability.
Astrocytes are highly branched cells with small bodies found both in white matter (fibrous astrocytes) as well as in grey matter (protoplasmic astrocytes). The podocytes of both fibrous and protoplasmic astrocytes not only encircle nerve fibres and neuronal somas (respectively), but they also surround the abluminal surface of the capillaries. At this point, the processes are referred to as perivascular endfeet.
A similar architectural construct exists in the peripheral nervous system that also limits the interaction between the peripheral nerves and circulating blood. This system is informally referred to as the blood-nerve barrier.
Blood-Cerebrospinal Fluid Barrier
There is a similar barrier system in place that acts as an interface between blood and cerebrospinal fluid. This is known as the blood-cerebrospinal fluid barrier. The main similarities between the blood-cerebrospinal fluid barrier and the blood-brain barrier are:
- Endothelial cells found in the capillary beds
- Circumferential basement membrane around the abluminal surface of the capillary
- And perivascular endfeet of the astrocytes also on the abluminal surface of the capillaries
The blood-cerebrospinal fluid barrier, however, also has fenestrated endothelial cells which allow easier passage of water, gases and lipophilic substances from the blood to the cerebrospinal fluid. Additionally, there are choroidal epithelial cells that are integral to the production of cerebrospinal fluid. Choroid epithelium consists of ciliated cuboidal cells, equipped with microvilli, encompassing capillary tufts. Although the choroid epithelium is continuous with the ependymal layer (simple ciliated columnar cells) of the ventricle, it contains more tight junctions and consequently act as an effective barrier between blood and cerebrospinal fluid.
There are regions of the brain where the blood-brain barrier is absent. This anatomical adaptation allows areas of the brain to monitor homeostatic changes within the systemic circulation. As a result, the brain is able to detect these changes and effect necessary protective physiological processes to mitigate these activities. There are seven such areas that are collectively referred to as the circumventricular organs. They can be further subdivided in secretory and sensory organs:
- Secretory organs, as the name suggests, are structures that release their products directly into the bloodstream or cerebrospinal fluid. The products may either be neurohormonal or other proteins. The secretory circumventricular organs include the neurohypophysis (posterior pituitary gland), pineal gland, subcommissural organ and median eminence.
- Neurohypophysis – is also known as the posterior pituitary gland. It is the region of the hypophysis cerebri that originates from neuroectoderm and stores hypothalamic hormones (namely oxytocin and vasopressin). Hormones are delivered to the posterior pituitary gland by way of nerve fibres travelling from the paraventricular and supraoptic hypothalamic nuclei.
- Pineal gland – is a pine-shaped organ situated in the posterior aspect of the third ventricle. It lies just superior to, and in the midline of, the corpora quadrigemina (superior and inferior colliculi). The gland is encapsulated and lobulated (internally). Its constituent cells – pinealocytes – produce and cyclically release melatonin with the oscillating circadian rhythm (which is regulated by the suprachiasmatic nucleus). The absence of a blood-brain barrier here allows melatonin to be secreted into the rich blood supply coming from the posterior choroidal artery (branch of the posterior communicating artery) and internal cerebral veins (tributary to the great vein of Galen).
- Subcommissural organ – is situated near to the caudal limit of the pineal recess (in the third ventricle) at the opening of the cerebral aqueduct of Sylvius. Here, it is caudally and ventrally related to the posterior commissure. The ependymal cells here, unlike those covering the other circumventricular organs, are tall ciliated columnar cells. The capillaries at this level are not as abundant or significantly fenestrated as those in other circumventricular organs. The subcommissural organ releases SCO-spondin, which is a glycoprotein that aggregates within the third ventricle and forms Reissner’s fibres. These fibres have been implicated in maintaining the patency of the aqueduct of Sylvius and their absence results in congenital hydrocephalus.
- Median Eminence – has an intricate communication with the hypophyseal portal system that permits communication between systemic circulation and cerebrospinal fluid by way of the large number of fenestrated capillary beds it contains. The median eminence, which is located at the floor of the hypothalamus, is anterior to the tuber cinereum (ventral extent of the third ventricle). The median eminence also contains specialized cells known as tanycytes, which assist in modifying the permeability of the membrane to allow macromolecules to enter the peripheral circulation.
- Sensory organs are responsible for monitoring the peripheral circulation and responding appropriately to reverse these changes or eliminate toxins. These organs include the subfornical organ, the organum vasculosum of the lamina terminalis and the area postrema.
- Subfornical organ – is a small region at the interventricular foramen of Monro that is comprised of glial cells, neurons and a densely packed tuft of fenestrated capillaries. Like other circumventricular organs, the subfornical organ is covered by flattened ependymal cells. The subfornical organ has multiple homeostatic functions, including cardiovascular regulation, osmoregulation and energy regulation, among others. This concept is supported by its efferent projections to the lateral hypothalamus, the median preoptic area and organum vasculosum.
- Organum vasculosum – also known as the organum vasculosum of the lamina terminalis (OVLT) or simply, the vascular organ, it is cranial to the optic chiasm and caudal to the anterior commissure. The vascular bed of this organ is highly fenestrated and the ependyma contains flattened cells with very sparsely distributed cilia. The primary role of the vascular organ is to regulate fluid balance. As such, it receives afferent fibres from the subfornical organ, several hypothalamic nuclei and the locus coeruleus. It then projects to the supraoptic and median preoptic nuclei.
- Area postrema – is probably the most commonly known circumventricular organ. It is a paired structure that is located at the caudal extent of the floor of the fourth ventricle. This bilateral structure is an important component of what is commonly termed the vomiting center. The absence of a blood-brain barrier in this location allows the area postrema to identify chemical irritants and stimulate a vomiting response.
During the first few days of life, the neonate is at risk for a treatable condition known as physiological jaundice. In utero, there is a high concentration of foetal haemoglobin (HbF) which is completely replaced by adult haemoglobin (HbA) by about six months of age. However, this subtype of haemoglobin has a relatively high turnover rate. A problem arises because the breakdown of haemoglobin results in the production of bilirubin. Haem is broken down by haem oxygenase to soluble biliverdin, which is then reduced to insoluble bilirubin by biliverdin reductase. Owing to its lipophilic nature, the insoluble bilirubin is able to cross lipid layers; including the blood-brain barrier. Fortunately, the carrier protein albumin typically binds to bilirubin to facilitate its transport in the vascular system to the liver for further processing. However, in cases where bilirubin levels exceed that of albumin (i.e. saturation of the carrier proteins), excess bilirubin can then travel to the CNS and cross the blood-brain barrier. If left untreated, this could result in a pathological condition known as kernicterus, which is a bilirubin induced neuropathy.
There is a commonly accepted notion that neonates are at a higher risk of brain toxicity secondary to neurotoxin exposure as a result of poorly developed blood-brain barriers. However, new studies suggest that the blood-brain barrier is adequately formed during early foetal life. The alternative explanation for greater susceptibility of neonates to brain injury from agents such as bilirubin is that there are more transport proteins present in the blood-cerebrospinal fluid barrier in neonates that is not observed in adult blood-cerebrospinal fluid barriers. As a result, these chemicals can gain access to the cerebrospinal fluid and from there, enter the brain. Additionally, unconjugated bilirubin is able to disrupt the tight junctions and gain access to the brain.
Insults to the brain either by hypertensive encephalopathy, status epilepticus, or ischaemia may render the blood-brain barrier defective for two to three weeks. This disruption of the barrier will allow molecules that were typically barred from contacting brain tissue to enter the microenvironment of the central nervous system. One proposition for the exact mechanism by which this occurs is that the insult results in endothelial damage and subsequent disruption of the tight junctions. Neoplastic lesions also provide a unique issue for the blood-brain barrier. One of the hallmarks of tumours is rapid angiogenesis. In the case of the barrier, the newly formed vessels, however, are devoid of a blood-brain barrier. Therefore, the tumour site also serves as a point of entry for neurotoxic agents to enter nervous tissue.