Products Cited in Publications Worldwide Establishing a Pertinent In vitro Model of the Blood Brain Barrier to Elucidate the Mechanisms of Invasion and Drug Permeability to the Brain

Establishing a Pertinent In vitro Model of the Blood Brain Barrier to Elucidate the Mechanisms of Invasion and Drug Permeability to the Brain

FATIMA FOUAD BALLOUT

Abstract

The maintenance of homeostasis in the brain relies on the restrictive permeability of theblood brain barrier (BBB). Neurological disorders, neurodegeneration, infectious insults.and tumor metastasis to the brain are all consequences of the loss of structural integrityof the BBB. Specific to Lebanon, 80% of the Lebanese population is thought to beinfected with Toxoplasma gondi (7, gondii). Chronic toxoplasmosis (CT) is establishedafter the parasite crosses the BBB to form cysts in the brain. The latter is associated withprimary neuropathies, neuropsychiatric and behavioral disorders as well as brain cancersFurthermore, 1 in 8 women will develop breast cancer in their lifetime. One of the mostdevastating consequences of breast cancer development and progression is secondarymetastasis to the brain, Hence, it is imperative to find a relevant way to study the BBB tocurb the deleterious side effects of it being breached. Current models fail to recapitulatethe fiundamental properties required to mirror the pathophysiological features ofthe BBBleaving a gap in the application and translation of the research for medical application.Therefore, there is a need for efective modeling of the BBB to elucidate mechanisms ofa variety of diseases including parasitic infection, metastasis of cancer to the brain, andto assess current drugs for BBB permeability and for novel drug screening. In this study.we developed a three-dimensional (3D) model that recapitulates the physiological andmolecular properties of the BBB in vitro. This was achieved using a trans-well, cell-celand cell-matrix interaction model. This model uniquely uses primary human endothelialcells and astrocytes, as well as subendothelial basement membrane to faithfully mimicthe cyto-architecture of the BBB. Barrier permeability was then assessed using transepithelial/ endothelial electrical resistance (TEER) and a variety of permeability tracers.We used this model as a platform to assess the invasion of Toxoplasma gondii (T. gondii)to the brain and breast cancer metastasis. This novel BBB model will contribute to theassessment of known drugs that are BBB permeable as well as discovering novel drugsthat can be delivered to the brain. In doing so, we hope to extricate the molecularmechanisms of these breaches of the BBB to contribute to the amelioration of theoutcomes of diagnoses of 7. gondii infection or metastatic breast cancer.

Keywords

Blood brain barrier ; parasitic infection ; breast cancer metastasis

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