Barriers in the brain: a renaissance?

The subarachnoid space, where cerebrospinal fluid (CSF) flows over the brain and spinal cord, is lined on one side by arachnoid barrier (AB) cells that form part of the blood-CSF barrier. However, despite the fact that drugs are administered into the CSF and CSF drug concentrations are used as a surrogate for brain drug concentration following systemic drug administration, the tightjunctioned AB cells have never been examined for whether they express drug transporters that would influence CSF and central nervous system drug disposition. Hence, we characterized drug transporter expression and function in AB cells. Immunohistochemical analysis showed P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in mouse AB cells but not other meningeal tissue. The Gene Expression Nervous System Atlas (GENSAT) database and the Allen Mouse Brain Atlas confirmed these observations. Microarray analysis of mouse and human arachnoidal tissue revealed expression of many drug transporters and some drug-metabolizing enzymes. Immortalized mouse AB cells express functional P-gp on the apical (dura-facing) membrane and BCRP on both apical and basal (CSF-facing) membranes. Thus, like blood-brain barrier cells and choroid plexus cells, AB cells highly express drug transport proteins and likely contribute to the blood-CSF drug permeation barrier.

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“…1) (Saunders et al, 2008). The BBB and CP also express drug transporters that affect drug penetration into the brain (Redzic, 2011).…”

Section: Introductionmentioning

confidence: 99%

Drug Transporters on Arachnoid Barrier Cells Contribute to the Blood–Cerebrospinal Fluid Barrier

et al. 2013

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“…BBB permeability is determined by the unique structure of the capillary endothelium allowing only for transcellular diffusion (small molecules, nutrients and fat soluble substances) or carrier facilitated active transport of regulatory proteins and hormones. In addition to its morphological, brain capillary endothelium acts also as a biochemical regulator, actively metabolizing certain regulatory molecules such as adrenaline or dopamine as well as some metabolites and toxins whose activity would otherwise disrupt homeostasis and affect brain function [18,19].…”

Section: Blood-brain Barrier As a Likely Factor In The Chemobrain Devmentioning

confidence: 99%

Chemobrain - A Troubling Side Effect of Chemotherapy

Banach¹,

Juranek²

2017

J Depress Anxiety

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The first mention of the term chemobrain appeared in the literature in response to a steady flow of clinical reports and research articles on neurological dysfunctions and so called "foggy brain" in chemotherapy treated cancer patients [1,2]. "Foggy brain" more precisely known as a cognitive impairment of the brain is a phenomenon with a long history in psychiatry and neurology, however its presence in cancer patients has not been reported until relatively recently. Cognitive impairment as a result of chemotherapy was first mentioned in the 70s but it was not until late 80s when it was clearly recognized. Over years more and more reports were providing solid evidence for a chemotherapy associated cognitive impairment in cancer patients [3,4]. Patients treated with chemotherapeutics were often complaining of visual memory lapses (impaired or delayed recognition of objects, pictures, shapes), verbal difficulties (difficulties with recalling names, concepts, definitions etc) and inability to focus on complex and multi-step tasks. The severity of the symptoms depends on the patient, ranging from mild, almost unnoticeable changes in brain function to severe, highly symptomatic neurological dysfunctions impairing patients' life [5,6].Chemobrain is the most prevalent in a population of cancer patients aged 65 years and above. Numerous studies show that the risk of cancer treatment related side effects, including chemobrain, increases with age. This is due not so much as to patients' chronological age, but rather stems from limited organ reserves, existing comorbidities, polypharmacy, nutritional status, emotional disorders and socioeconomic status of these patients [7,8].The etiology of these chemotherapy associated cognitive impairments remains unclear. Reports from animal studies on chemotherapy associated brain dysfunctions indicate that chemobrain might be a results of a number of intertwined molecular and genetic factors such as: increased permeability of blood -brain barrier (BBB), altered activity of plasma membrane pumps within central nervous system (CNS), DNA damage, telomere shortening, dysfunction of cytokine secretion, impaired neuronal regeneration and oxidative stress [9,10]. Some studies also indicate that chemobrain might result from a combination of vascular (vascular lesions, anemia) and immune deficiencies (increased inflammation at the injection site, severe immune response) as well as altered expression of apo-lipoprotein E gene, involved in the development of Alzheimer's disease [11]. DiscussionRecent studies on patients treated with different chemotherapeutics shed some light on possible mechanisms of chemotherapy associated cognitive impairments. For example, it has been shown that doxorubicin, a common drug for a variety of different types of cancer, causes oxidative damage to neutrophil mitochondria likely contributing to the development of cognitive dysfunctions [9,12]. Furthermore, studies on neurotoxicity of 5-fluorouracil, one of the essential medicines listed by WHO, revealed that it red...

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“…In addition to this physiological barrier, drugs are rapidly cleared by efflux pumps such as P-glycoprotein, and a rapid turnover rate of extracellular fluid in the brain. In combination, these factors have limited the number of successful pharmacologic treatments for diseases of the brain and necessitate a closer examination of both traditional and novel methods of drug delivery (Choi et al, 2008;Eyal et al, 2009;Saunders et al, 2008). In brain tumors such as GBM, the BBB is progressively disrupted with tumor growth by inducing large gaps between endothelial cells (Coomber et al, 1985).…”

Section: The Bbb: An Obstacle For Drug Delivery To Brain Tumormentioning

confidence: 99%

“…These include i) intra-arterial administration, ii) packaging drugs such as microcapsules and liposomes, iii) use of biologically active agents (such as bradykinin and histamine) (Greenwood, 1992), iv) use of replication-competent retroviruses to deliver oncolytic therapies (Tai & Kasahara, 2008), v) use of mesenchymal (Yong et al, 2009) or neural stem cells to deliver small molecules, antibodies, or toxic payloads (Aboody et al, 2000;Frank et al, 2009). There are also several specific transport mechanisms that have been exploited, involving the activity of several independent transporters that mediate the flux of substances important for brain function, such as carrier-mediated transporters, including the glucose and amino acid transporters (Rapoport, 1996;Tamai & Tsuji, 1996;Deeken & Loscher, 2007;Saunders et al, 2008), active efflux transporters, including P-glycoprotein and the other ATP-binding cassette (ABC) gene family members, and receptor-mediated transporters, of which transferrin receptor (TfR), insulin receptor, and low-density lipoprotein receptor (Pardridge, 2007). A further strategy has been to conjugate the therapeutic drug with a protein or a monoclonal antibody that gains access to the brain by receptor-mediated transcytosis (Pardridge, 1999).…”

Section: Intravascular Deliverymentioning

confidence: 99%

New Therapeutic Strategies for the Treatment of Brain Tumor

Hashizume¹

2011

Brain Tumors - Current and Emerging Therapeutic Strategies

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Barriers in the brain: a renaissance?

Cited by 203 publications

References 55 publications

Drug Transporters on Arachnoid Barrier Cells Contribute to the Blood–Cerebrospinal Fluid Barrier

Drug Transporters on Arachnoid Barrier Cells Contribute to the Blood–Cerebrospinal Fluid Barrier

Chemobrain - A Troubling Side Effect of Chemotherapy

New Therapeutic Strategies for the Treatment of Brain Tumor

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