Bumetanide decreases canine cerebrospinal fluid production. In vivo evidence for NaCl cotransport in the central nervous system.

Javaheri, Shahrokh; Wagner, Kenneth R.

doi:10.1172/jci116829

Cited by 68 publications

(59 citation statements)

References 28 publications

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“…It would thus be interesting to investigate the long-term effects of ion transport changes on CSF dynamics. Inhibition of the three main transporters investigated in this study has previously been reported to inhibit CSF production (25)(26)(27)(37)(38). We have shown a decrease in expression of the Na ϩ -H ϩ exchanger and a probable increase in phosphorylation of the Na ϩ -K ϩ -ATPase ␣1-subunit.…”

Section: Figsupporting

confidence: 61%

Differential Effects of Diabetes on Rat Choroid Plexus Ion Transporter Expression

Egleton

Campos²,

Huber³

et al. 2003

Diabetes

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Though diabetes is a disease with vascular complications, little is known about its effects on the blood-brain barrier or the blood-cerebrospinal fluid barrier (BCSFB). The BCSFB is situated at choroid plexuses located in the lateral, third, and fourth ventricles. Choroid plexuses are the primary site of cerebrospinal fluid (CSF) production and express numerous ion transporters. Previous studies have shown a perturbation of ion transport in the periphery and brain during diabetes. In this study, we investigated the effect of diabetes on ion transporters in the choroid plexuses of streptozotocin (STZ)-induced diabetic rats. Diabetes was induced in male Sprague-Dawley rats by intraperitoneal injection of STZ (60 mg/kg in citrate buffer, confirmed by glucose analysis: 601 ؎ 22 mg/dl diabetic rats, 181 ؎ 46 mg/dl age-matched controls); and at 28 days, rats were killed, choroid plexuses harvested, and protein extracted. Western blot analyses were carried out using antibodies for ion transporters, including Na ؉ -K ؉ -2Cl ؊ cotransporter and the Na iabetes is a disease with numerous vascular complications. Previous studies have shown perturbations in ion transport in both the periphery and the brain during diabetes (1-3). Though diabetes is a vascular disease, little is known regarding the effects of diabetes on the blood-brain barrier (BBB) or the blood-cerebrospinal fluid barrier (BCSFB). It has been reported that diabetes is a risk factor not only for stroke (4,5), but also for normal-pressure hydrocephalus (6,7). Hydrocephalus is caused by excessive retention or production of cerebrospinal fluid (CSF) within the central nervous system. CSF is produced by the choroidal epithelial cells of the choroid plexus (8). The choroid plexuses are also the site of the BCSFB and are located in the lateral, third, and fourth ventricles. Capillaries of the choroid plexus are fenestrated, allowing extracellular fluid formation (unlike other brain capillary beds). CSF production involves the combination of a number of transport systems in the choroid plexus (9) (Fig. 1).Animal models of diabetes have shown that the Na (13), and Na ϩ -K ϩ -ATPase (14 -17) have altered expression and activity in a number of vascular beds. These three transporters are critical for CSF production and pH maintenance (9). In this study, we have investigated the effects of the streptozotocin (STZ) model of type 1 diabetes on expression of the Na ϩ -H ϩ exchanger, NaϪ cotransporter, and Na ϩ -K ϩ -ATPase in the rat choroid plexus. RESEARCH DESIGN AND METHODS Induction of diabetes.All protocols used in this study were approved by the University of Arizona Institutional Animal Care and Use Committee and abide by National Institutes of Health guidelines. Diabetes was induced in male 300-to 325-g Sprague-Dawley rats (Harlan, Indianapolis, IN) via an intraperitoneal injection of 60 mg/kg STZ (Sigma, St. Louis, MO) in sterile phosphate buffered saline. Control animals were injected intraperitoneally with phosphate buffered saline. The animals were housed under ...

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Section: Figsupporting

confidence: 61%

Differential Effects of Diabetes on Rat Choroid Plexus Ion Transporter Expression

Egleton

Campos²,

Huber³

et al. 2003

Diabetes

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“…channels. In the pharmacology category, particularly useful have been diuretic agents that reduce CSF formation by slowing ion transport across CP (Davson and Segal, 1970;Javaheri and Wagner, 1993;McCarthy and Reed, 1974;Murphy and Johanson, 1990;Praetorius and Nielsen, 2006;Johanson, 1980, 1991). Clearly, the pharmacologic inhibitory linkage in the CP-CSF nexus is consistent with physiologic coupling of CP ion transport to CSF formation.…”

Section: Cerebrospinal Fluid Secretion By Cpmentioning

confidence: 99%

A balanced view of choroid plexus structure and function: Focus on adult humans

Spector

Keep

Snodgrass

et al. 2015

Experimental Neurology

184

170

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Recently tremendous progress has been made in studying choroid plexus (CP) physiology and pathophysiology; and correcting several misconceptions about the CP. Specifically, the details of how CP, a locus of the blood-CSF barrier (BCSFB), secretes and purifies CSF, generates intracranial pressure (ICP), maintains CSF ion homeostasis, and provides micronutrients, proteins and hormones for neuronal and glial development, maintenance and function, are being understood on a molecular level. Unequivocal evidence that the CP secretory epithelium is the predominant supplier of CSF for the ventricles comes from multiple lines: uptake kinetics of tracer (22)Na and (36)Cl penetration from blood to CSF, autoradiographic mapping of rapid (22)Na and (36)Cl permeation (high permeability coefficients) into the cerebroventricles, CSF sampling from several different in vivo and in vitro CP preparations, CP hyperplasia that increases CSF formation and ICP; and in vitro analysis of CP ability to transport molecules (with expected directionality) and actively secrete fluid against an hydrostatic fluid column. Furthermore, clinical support for this CP-CSF model comes from neurosurgical procedures to remove lateral ventricle CPs in hydrocephalic children to reduce CSF formation, thereby relieving elevated ICP. In terms of micronutrient transport, ascorbic acid, folate and other essential factors are transported by specific (cloned) carriers across CP into ventricular CSF, from which they penetrate across the ependyma and pia mater deeply into the brain to support its viability and function. Without these choroidal functions, severe neurological disease and even death can occur. In terms of efflux or clearance transport, the active carriers (many of which have been cloned and expressed) in the CP basolateral and apical membranes perform regulatory removal of some metabolites (e.g. choline) and certain drugs (e.g. antibiotics like penicillin) from CSF, thus reducing agents such as penicillin to sub-therapeutic levels. Altogether, these multiple transport and secretory functions in CP support CSF homeostasis and fluid dynamics essential for brain function.

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“…Bumetanide (an NKCC1 inhibitor) and furosemide (a KCC inhibitor), alone or in combination with acetazolamide, have been documented to decrease CSF production in canine and feline models. 65,70 The effect of bumetanide on CSF production, in conjunction with its selectivity for NKCC1, highlights the importance of this transporter in CSF homeostasis. Animal evidence also reveals the effect of furosemide in disrupting ion transport across the blood-CSF barrier, which reduces the rate of CSF secretion.…”

Section: Medical Management Of Hydrocephalus By Targeting Csf Productionmentioning

confidence: 99%

Cerebrospinal fluid hypersecretion in pediatric hydrocephalus

Karimy¹,

Durán²,

Hu³

et al. 2016

FOC

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Hydrocephalus, despite its heterogeneous causes, is ultimately a disease of disordered CSF homeostasis that results in pathological expansion of the cerebral ventricles. Our current understanding of the pathophysiology of hydrocephalus is inadequate but evolving. Over this past century, the majority of hydrocephalus cases has been explained by functional or anatomical obstructions to bulk CSF flow. More recently, hydrodynamic models of hydrocephalus have emphasized the role of abnormal intracranial pulsations in disease pathogenesis. Here, the authors review the molecular mechanisms of CSF secretion by the choroid plexus epithelium, the most efficient and actively secreting epithelium in the human body, and provide experimental and clinical evidence for the role of increased CSF production in hydrocephalus. Although the choroid plexus epithelium might have only an indirect influence on the pathogenesis of many types of pediatric hydrocephalus, the ability to modify CSF secretion with drugs newer than acetazolamide or furosemide would be an invaluable component of future therapies to alleviate permanent shunt dependence. Investigation into the human genetics of developmental hydrocephalus and choroid plexus hyperplasia, and the molecular physiology of the ion channels and transporters responsible for CSF secretion, might yield novel targets that could be exploited for pharmacotherapeutic intervention.

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Bumetanide decreases canine cerebrospinal fluid production. In vivo evidence for NaCl cotransport in the central nervous system.

Cited by 68 publications

References 28 publications

Differential Effects of Diabetes on Rat Choroid Plexus Ion Transporter Expression

Differential Effects of Diabetes on Rat Choroid Plexus Ion Transporter Expression

A balanced view of choroid plexus structure and function: Focus on adult humans

Cerebrospinal fluid hypersecretion in pediatric hydrocephalus

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