Blood-brain barrier

The passage of water-soluble substances from the blood to the CNS is limited by tight junctions (zonulae occludentes) which are found between brain capillary endothelial cells, limiting penetration of the cerebral parenchyma (blood-brain barrier, BBB), as well as between choroid plexus epithelial cells (blood-CSF barrier) 1).

A number of specialized mediated transport systems allow transmission of, among other things, glucose and certain amino acids (especially precursors to neurotransmitters).

The efficacy of the Blood-brain barrier is compromised in certain pathological states (e.g. tumor, infection, trauma, stroke, hepatic encephalopathy…), and can also be manipulated pharmacologically (e.g. hypertonic mannitol increases the permeability, whereas steroids reduce the penetration of small hydrophilic molecules).

The BBB is absent in the following areas: choroid plexus, hypophysis, tuber cinereum, area postrema, pineal and preoptic recess.

Means of assessing the integrity of the BBB:

● visible dyes: Evan’s blue, fluorescein

● radioopaque dyes (imaged with CT scan 2)): iodine (protein-bound contrast agent)

● paramagnetic (imaged on MRI): gadolinium (protein-bound contrast agent)

● microscopic: horseradish peroxidase

● radiolabeled: albumin, sucrose

Traditionally, the BBB has been considered to be a major hindrance to the use of chemotherapy for brain tumors. In theory, the BBB selectively excludes many chemotherapeutic agents from the CNS, thereby creating a “safe haven” for some tumors, e.g. metastases.

This concept has been challenged 3). Regardless of the etiology, the response of most brain tumors to systemic chemotherapy is usually very modest, with a notable exception being a favorable response of oligodendrogliomas and gliomas lacking MGMT activity.

The blood brain barrier (BBB) is a highly selective permeability barrier that separates the circulating blood from the brain extracellular fluid (BECF) in the central nervous system (CNS).

The blood-brain barrier is formed by capillary endothelial cells, which are connected by tight junctions with an extremely high electrical resistance of at least 1000Ωcm-2.

The blood-brain barrier allows the passage of water, some gases, and lipid soluble molecules by passive diffusion, as well as the selective transport of molecules such as glucose and amino acids that are crucial to neural function. On the other hand, the blood-brain barrier may prevent the entry of lipophilic, potential neurotoxins by way of an active transport mechanism mediated by P-glycoprotein. Astrocytes are necessary to create the blood-brain barrier. A small number of regions in the brain, including the circumventricular organs (CVOs), do not have a blood-brain barrier.

The blood-brain barrier occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation.

Endothelial cells restrict the diffusion of microscopic objects (e.g., bacteria) and large or hydrophilic molecules into the cerebrospinal fluid (CSF), while allowing the diffusion of small hydrophobic molecules (O2, CO2, hormones).

Cells of the barrier actively transport metabolic products such as glucose across the barrier with specific proteins.

This barrier also includes a thick basement membrane and astrocytic end feet.

Drug delivery to the central nervous system (CNS) is complicated by the blood-brain barrier. As a result, many agents that are found to be potentially effective at their site of action cannot be sufficiently or effectively delivered to the CNS and therefore have been discarded and not developed further for clinical use, leaving many CNS diseases untreated. One way to overcome this obstacle is intracerebroventricular (ICV) delivery of the therapeutics directly to cerebrospinal fluid (CSF). Recent experimental and clinical findings reveal that CSF flows from the ventricles throughout the parenchyma towards the subarachnoid space also named minor CSF pathway, while earlier, it was suggested that only in pathological conditions such as hydrocephalus this form of CSF flow occurs. This transependymal flow of CSF provides a route to distribute ICV-infused drugs throughout the brain. More insight on transependymal CSF flow will direct more rational to ICV drug delivery and broaden its clinical indications in managing CNS diseases 4).

The blood-brain barrier represents a fundamental limitation in treating neurological disease because it prevents all neuropeptides from reaching the central nervous system (CNS). Currently, there is no efficient method to permanently bypass the blood-brain barrier.

Although ongoing research has yielded some potential options for future glioblastoma therapies, delivery of chemotherapy medications across the BBB remains elusive and has limited the efficacy of these medications 5).

Current strategies for enhancing the delivery of therapies across the BBB to the tumor is discussed, with a distinction made between strategies that seek to disrupt the BBB and those that aim to circumvent it in the article of Azad et al. 6).

Histological investigations have shown that disruption of the blood brain barrier (BBB) is well correlated with the degradation of collagen IV, a major component of the BBB 7). Among other basal lamina proteins, collagen IV is often degraded by metalloproteinase-9 (MMP-9)

Triolein emulsion infusion into the carotid artery has been reported to induce temporary and reversible opening of the blood brain barrier by increasing vascular permeability.

Transmucosal delivery of glial derived neurotrophic factor (GDNF) is equivalent to direct intrastriatal injection at ameliorating the behavioral and immunohistological features of Parkinson disease in a murine model. Mucosal grafting of arachnoid defects is a technique commonly used for endoscopic skull base reconstruction and may represent a novel method to permanently bypass the blood-brain barrier 8).

Blood-brain barrier and chemotherapy agents.

Neuwelt EA, Barnett PA, McCormick CI, et al. Osmotic Blood-Brain Barrier Modification: Monoclonal Antibody, Albumin, and Methotrexate Delivery to Cerebrospinal Fluid and Brain. Neurosurgery. 1985; 17:419–423
Neuwelt EA, Maravilla KR, Frenkel EP, et al. Use of Enhanced Computerized Tomography to Evaluate Osmotic Blood-Brain Barrier Disruption. Neurosurgery. 1980; 6:49–56
Stewart DJ. A Critique of the Role of the Blood-Brain Barrier in the Chemotherapy of Human Brain Tumors. JNeurooncol. 1994:121–139
Casaca-Carreira J, Temel Y, Hescham SA, Jahanshahi A. Transependymal Cerebrospinal Fluid Flow: Opportunity for Drug Delivery? Mol Neurobiol. 2017 Apr 28. doi: 10.1007/s12035-017-0501-y. [Epub ahead of print] PubMed PMID: 28455692.
Hendricks BK, Cohen-Gadol AA, Miller JC. Novel delivery methods bypassing the blood-brain and blood-tumor barriers. Neurosurg Focus. 2015 Mar;38(3):E10. doi: 10.3171/2015.1.FOCUS14767. PubMed PMID: 25727219.
Azad TD, Pan J, Connolly ID, Remington A, Wilson CM, Grant GA. Therapeutic strategies to improve drug delivery across the blood-brain barrier. Neurosurg Focus. 2015 Mar;38(3):E9. doi: 10.3171/2014.12.FOCUS14758. PubMed PMID: 25727231.
Egashira Y, Zhao H, Hua Y, Keep RF, Xi G. White matter injury after subarachnoid hemorrhage: role of blood-brain barrier disruption and matrix metalloproteinase-9. Stroke. 2015;46(10):2909–2915.
Bleier BS, Kohman RE, Guerra K, Nocera AL, Ramanlal S, Kocharyan AH, Curry WT, Han X. Heterotopic Mucosal Grafting Enables the Delivery of Therapeutic Neuropeptides Across the Blood Brain Barrier. Neurosurgery. 2016 Mar;78(3):448-57. doi: 10.1227/NEU.0000000000001016. PubMed PMID: 26352099.
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