The Choroid Plexus—CSF Nexus

Johanson, Conrad E.

doi:10.1007/978-1-59259-371-2_8

Cited by 10 publications

(15 citation statements)

References 14 publications

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“…The regulation of drug disposition into the brain and wider CNS is tightly governed by the impermeable nature of the BBB and BCSFB coupled with an increasingly important complement of drug transporter proteins which tightly regulate the brain and CNS microenvironment (2,3,(7)(8)(9)(10)(11)(12)84 A novel class of compounds that have gained interest as potential transporter modulation candidates are phytoestrogens, of which flavonoids are the most abundant class. In this context, this study was designed to examine the impact of, primarily, flavonoid exposure on the expression and function of BCRP at the BCSFB using the rat choroid plexus Z310 cells lines which has previously been shown to express P-gp , MRP1 (80, 89) and BCRP (37).…”

Section: Discussionmentioning

confidence: 99%

“…The CP epithelium is a dynamic tissue which has a greater perfusion rate compared to the cerebral blood flow and weighing only 2 g (3-6). It secretes CSF at a rate of 25 mL/hour in humans (7) which helps to maintain brain extracellular fluid (ECF) and CSF homeostasis (2,8) as well as providing mechanical support to the brain, removal of metabolic products (9) and as a route for the distribution of nutrients, neurotransmitters and hormones across the CNS (10,11) (12,13).…”

Section: Introductionmentioning

confidence: 99%

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Phytoestrogens Modulate Breast Cancer Resistance Protein Expression and Function at the Blood-Cerebrospinal Fluid Barrier

Kaur

Badhan

2015

J Pharm Pharm Sci

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-PURPOSE: Breast cancer resistance protein (BCRP/ABCG2) is a drug efflux transporter expressed at the blood cerebrospinal fluid barrier (BCSFB), and influences distribution of drugs into the central nervous systems (CNS). Current inhibitors have failed clinically due to neurotoxicity. Novel approaches are needed to identify new modulators to enhance CNS delivery. This study examines 18 compounds (mainly phytoestrogens) as modulators of the expression/function of BCRP in an in vitro rat choroid plexus BCSFB model. METHODS: Modulators were initially subject to cytotoxicity (MTT) assessment to determine optimal non-toxic concentrations. Reverse-transcriptase PCR and confocal microscopy were used to identify the presence of BCRP in Z310 cells. Thereafter modulation of the intracellular accumulation of the fluorescent BCRP probe substrate Hoechst 33342 (H33342), changes in protein expression of BCRP (western blotting) and the functional activity of BCRP (membrane insert model) were assessed under modulator exposure. RESULTS: A 24 hour cytotoxicity assay (0.001 µM-1000 µM) demonstrated the majority of modulators possessed a cellular viability IC50 > 148 µM. Intracellular accumulation of H33342 was significantly increased in the presence of the known BCRP inhibitor Ko143 and, following a 24 hour pre-incubation, all modulators demonstrated statistically significant increases in H33342 accumulation (P < 0.001), when compared to control and Ko143. After a 24 hour pre-incubation with modulators alone, a 0.16-2.5 -fold change in BCRP expression was observed for test compounds. The functional consequences of this were confirmed in a permeable insert model of the BCSFB which demonstrated that 17-β-estradiol, naringin and silymarin (down-regulators) and baicalin (up-regulator) can modulate BCRP-mediated transport function at the BCSFB. CONCLUSION: We have successfully confirmed the gene and protein expression of BCRP in Z310 cells and demonstrated the potential for phytoestrogen modulators to influence the functionality of BCRP at the BCSFB and thereby potentially allowing manipulation of CNS drug disposition.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phytoestrogens Modulate Breast Cancer Resistance Protein Expression and Function at the Blood-Cerebrospinal Fluid Barrier

Kaur

Badhan

2015

J Pharm Pharm Sci

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“…2) down the ventriculo-cisternal axis [27]. Actively formed CSF stems from coordinated secretion of solutes across the thin epithelial interface (Fig.…”

Section: Csf Formationmentioning

confidence: 99%

“…Because the CP is a kidney-type organ [34], with epithelial mechanisms [35] similar to those in the renal tubule that transfer a large volume of ions and water, many diuretic agents have been tested for ability to inhibit CSF formation [1,27]. Gaining insight on the many ion transporters and channels in CPe is key to attaining fine control of CSF production, upward as well as downward regulation.…”

Section: Csf Formationmentioning

confidence: 99%

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Multiplicity of cerebrospinal fluid functions: New challenges in health and disease

Johanson

Duncan

Klinge

et al. 2008

Fluids Barriers CNS

713

704

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This review integrates eight aspects of cerebrospinal fluid (CSF) circulatory dynamics: formation rate, pressure, flow, volume, turnover rate, composition, recycling and reabsorption. Novel ways to modulate CSF formation emanate from recent analyses of choroid plexus transcription factors (E2F5), ion transporters (NaHCO3 cotransport), transport enzymes (isoforms of carbonic anhydrase), aquaporin 1 regulation, and plasticity of receptors for fluid-regulating neuropeptides. A greater appreciation of CSF pressure (CSFP) is being generated by fresh insights on peptidergic regulatory servomechanisms, the role of dysfunctional ependyma and circumventricular organs in causing congenital hydrocephalus, and the clinical use of algorithms to delineate CSFP waveforms for diagnostic and prognostic utility. Increasing attention focuses on CSF flow: how it impacts cerebral metabolism and hemodynamics, neural stem cell progression in the subventricular zone, and catabolite/peptide clearance from the CNS. The pathophysiological significance of changes in CSF volume is assessed from the respective viewpoints of hemodynamics (choroid plexus blood flow and pulsatility), hydrodynamics (choroidal hypo- and hypersecretion) and neuroendocrine factors (i.e., coordinated regulation by atrial natriuretic peptide, arginine vasopressin and basic fibroblast growth factor). In aging, normal pressure hydrocephalus and Alzheimer's disease, the expanding CSF space reduces the CSF turnover rate, thus compromising the CSF sink action to clear harmful metabolites (e.g., amyloid) from the CNS. Dwindling CSF dynamics greatly harms the interstitial environment of neurons. Accordingly the altered CSF composition in neurodegenerative diseases and senescence, because of adverse effects on neural processes and cognition, needs more effective clinical management. CSF recycling between subarachnoid space, brain and ventricles promotes interstitial fluid (ISF) convection with both trophic and excretory benefits. Finally, CSF reabsorption via multiple pathways (olfactory and spinal arachnoidal bulk flow) is likely complemented by fluid clearance across capillary walls (aquaporin 4) and arachnoid villi when CSFP and fluid retention are markedly elevated. A model is presented that links CSF and ISF homeostasis to coordinated fluxes of water and solutes at both the blood-CSF and blood-brain transport interfaces.Outline1 Overview2 CSF formation2.1 Transcription factors2.2 Ion transporters2.3 Enzymes that modulate transport2.4 Aquaporins or water channels2.5 Receptors for neuropeptides3 CSF pressure3.1 Servomechanism regulatory hypothesis3.2 Ontogeny of CSF pressure generation3.3 Congenital hydrocephalus and periventricular regions3.4 Brain response to elevated CSF pressure3.5 Advances in measuring CSF waveforms4 CSF flow4.1 CSF flow and brain metabolism4.2 Flow effects on fetal germinal matrix4.3 Decreasing CSF flow in aging CNS4.4 Refinement of non-invasive flow measurements5 CSF volume5.1 Hemodynamic factors5.2 Hydrodynamic factors5.3 Neuroendocrine factors6 CS...

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CSF markers in sleep neurobiology

Martínez-Rodríguez

Santamaría

2005

Clinica Chimica Acta

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The Choroid Plexus—CSF Nexus

Cited by 10 publications

References 14 publications

Phytoestrogens Modulate Breast Cancer Resistance Protein Expression and Function at the Blood-Cerebrospinal Fluid Barrier

Phytoestrogens Modulate Breast Cancer Resistance Protein Expression and Function at the Blood-Cerebrospinal Fluid Barrier

Multiplicity of cerebrospinal fluid functions: New challenges in health and disease

CSF markers in sleep neurobiology

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