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https://www.readbyqxmd.com/read/28192112/multiple-blood-brain-barrier-transport-mechanisms-limit-bumetanide-accumulation-and-therapeutic-potential-in-the-mammalian-brain
#1
Kerstin Römermann, Maren Fedrowitz, Philip Hampel, Edith Kaczmarek, Kathrin Töllner, Thomas Erker, Douglas H Sweet, Wolfgang Löscher
There is accumulating evidence that bumetanide, which has been used over decades as a potent loop diuretic, also exerts effects on brain disorders, including autism, neonatal seizures, and epilepsy, which are not related to its effects on the kidney but rather mediated by inhibition of the neuronal Na-K-Cl cotransporter isoform NKCC1. However, following systemic administration, brain levels of bumetanide are typically below those needed to inhibit NKCC1, which critically limits its clinical use for treating brain disorders...
February 10, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28161194/bumetanide-reduce-the-seizure-susceptibility-induced-by-pentylenetetrazol-via-inhibition-of-aberrant-hippocampal-neurogenesis-in-neonatal-rats-after-hypoxia-ischemia
#2
Jiang-Jian Hu, Xing-Liang Yang, Wen-Di Luo, Song Han, Jun Yin, Wan-Hong Liu, Xiao-Hua He, Bi-Wen Peng
Hypoxia-ischemia brain damage (HIBD) is one of prevalent causes of neonatal mortality and morbidity. Our data demonstrated that hypoxia-ischemia (HI) induced Na(+)-K(+)-Cl(-)-co-transporter 1 (NKCC1) increasing in hippocampus. Previous studies demonstrated that NKCC1 regulates various stages of neurogenesis. In this study, we studied the role of increased NKCC1 in regulating of HI-induced neurogenesis. HIBD model was established in 7days old Sprague-Dawley rat pup, and the expression of NKCC1 was detected by western blot and qPCR...
February 2, 2017: Brain Research Bulletin
https://www.readbyqxmd.com/read/28146071/actions-of-quercetin-a-polyphenol-on-blood-pressure
#3
REVIEW
Yoshinori Marunaka, Rie Marunaka, Hongxin Sun, Toshiro Yamamoto, Narisato Kanamura, Toshio Inui, Akiyuki Taruno
Disorder of blood pressure control causes serious diseases in the cardiovascular system. This review focuses on the anti-hypertensive action of quercetin, a flavonoid, which is one of the polyphenols characterized as the compounds containing large multiples of phenol structural units, by varying the values of various blood pressure regulatory factors, such as vascular compliance, peripheral vascular resistance, and total blood volume via anti-inflammatory and anti-oxidant actions. In addition to the anti-inflammatory and anti-oxidant actions of quercetin, we especially describe a novel mechanism of quercetin's action on the cytosolic Cl(-) concentration ([Cl(-)]c) and novel roles of the cytosolic Cl(-) i...
January 29, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28110691/is-insulin-growth-factor-1-the-future-for-treating-autism-spectrum-disorder-and-or-schizophrenia
#4
Rami Bou Khalil
To date, no curative psychopharmacologic treatment exists for the core symptoms of autism spectrum disorder (ASD) as well as for schizophrenia. Bumatenide is a specific antagonist of the first isoform of the Na-K-Cl cotransporter (NKCC1). It is usually used as a diuretic but may also promote a decrease in intraneuronal chloride ion concentration leading to hyperpolarization in neuronal membrane and subsequent decrease in neuronal hyperexcitability. This physiologic effect has been considered to be behind the relative efficacy of bumetanide in improving symptoms of ASD and, to a lesser extent, schizophrenia...
February 2017: Medical Hypotheses
https://www.readbyqxmd.com/read/28100217/variation-in-branchial-expression-among-insulin-like-growth-factor-binding-proteins-igfbps-during-atlantic-salmon-smoltification-and-seawater-exposure
#5
Jason P Breves, Chelsea K Fujimoto, Silas K Phipps-Costin, Ingibjörg E Einarsdottir, Björn Thrandur Björnsson, Stephen D McCormick
BACKGROUND: In preparation for migration from freshwater to marine habitats, Atlantic salmon (Salmo salar L.) undergo smoltification, a transformation that includes the acquisition of hyposmoregulatory capacity. The growth hormone (Gh)/insulin-like growth-factor (Igf) axis promotes the development of branchial ionoregulatory functions that underlie ion secretion. Igfs interact with a suite of Igf binding proteins (Igfbps) that modulate hormone activity. In Atlantic salmon smolts, igfbp4,-5a,-5b1,-5b2,-6b1 and-6b2 transcripts are highly expressed in gill...
January 18, 2017: BMC Physiology
https://www.readbyqxmd.com/read/28087701/the-ubiquitin-ligase-nedd4l-regulates-the-na-k-2cl-co-transporter-nkcc1-slc12a2-in-the-colon
#6
Chong Jiang, Hiroshi Kawabe, Daniela Rotin
The ubiquitin ligase Nedd4-like (Nedd4L, or Nedd4-2) binds to and regulates stability of the epithelial Na+ channel (ENaC) in salt absorbing epithelia in the kidney, lung, and other tissues. Its role in the distal colon, which also absorbs salt and fluid and expresses ENaC, is unknown. Using conditional knockout approach to knockout Nedd4L in mice intestinal epithelium (Nedd4Lf/f;Vil-CreERT2) we show here that Nedd4L depletion leads to a higher steady-state short circuit current (Isc) in mouse distal colon tissue relative to controls...
January 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28074534/depolarizing-gaba-contributes-to-glutamatergic-network-rewiring-in-epilepsy
#7
Nazim Kourdougli, Christophe Pellegrino, Juho-Matti Renko, Stanislav Khirug, Geneviève Chazal, Tiina-Kaisa Kukko-Lukjanov, Sari E Lauri, Jean-Luc Gaiarsa, Liang Zhou, Angélique Peret, Eero Castrén, Raimo Kalevi Tuominen, Valérie Crépel, Claudio Rivera
OBJECTIVE: Rewiring of excitatory glutamatergic neuronal circuits is a major abnormality in epilepsy. Besides the rewiring of excitatory circuit, an abnormal depolarizing GABAergic drive has been hypothesized to participate in the epileptogenic processes. However, a remaining clinically relevant question is whether early post Status Epilepticus (SE) evoked chloride dysregulation is important for the remodeling of aberrant glutamatergic neuronal circuit. METHODS: Osmotic mini-pumps were used to infuse intracerebrally a specific inhibitor of depolarizing GABAergic transmission as well as a functionally blocking antibody towards the pan-neurotrophin receptor p75 (p75(NTR) )...
January 11, 2017: Annals of Neurology
https://www.readbyqxmd.com/read/28057537/the-chloride-co-transporters-nkcc1-and-kcc2-in-experimental-autoimmune-encephalomyelitis-eae
#8
Muhammad Saad Yousuf, Kasia Zubkow, Gustavo Tenorio, Bradley Kerr
Patients with multiple sclerosis (MS) often complain of neuropathic pain. According to the Gate Control Theory of Pain, spinal networks of GABAergic inhibitory interneurons are important in modulating nociceptive inputs from the periphery. Na+-K+-2Cl- co-transporter 1 (NKCC1) and K+-Cl- co-transporter 2 (KCC2) generally dictate the tone of GABA/glycine inhibition by regulating intracellular chloride concentrations. In this study, we investigated the role of NKCC1 and KCC2 in neuropathic pain observed in the animal model, experimental autoimmune encephalomyelitis (EAE), a commonly used model to study the pathophysiology of MS...
March 6, 2017: Neuroscience
https://www.readbyqxmd.com/read/28039063/encapsulation-of-primary-salivary-gland-cells-in-enzymatically-degradable-poly-ethylene-glycol-hydrogels-promotes-acinar-cell-characteristics
#9
Andrew D Shubin, Timothy J Felong, Brittany E Schutrum, Debria S L Joe, Catherine E Ovitt, Danielle S W Benoit
: Radiation therapy for head and neck cancers leads to permanent xerostomia due to the loss of secretory acinar cells in the salivary glands. Regenerative treatments utilizing primary submandibular gland (SMG) cells show modest improvements in salivary secretory function, but there is limited evidence of salivary gland regeneration. We have recently shown that poly(ethylene glycol) (PEG) hydrogels can support the survival and proliferation of SMG cells as multicellular spheres in vitro...
December 27, 2016: Acta Biomaterialia
https://www.readbyqxmd.com/read/28027400/elevated-intracellular-na-concentrations-in-developing-spinal-neurons
#10
Casie Lindsly, Carlos Gonzalez-Islas, Peter Wenner
Over 25 years ago it was first reported that intracellular chloride levels (Cl(-)in ) were higher in developing neurons than in maturity. This finding has had significant implications for understanding the excitability of developing networks and recognizing the underlying causes of hyperexcitability associated with disease and neural injury. While there is some evidence that intracellular sodium levels (Na(+)in ) change during the development of non-neural cells, it has largely been assumed that Na(+)in is the same in developing and mature neurons...
March 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27995646/bicarbonate-rich-fluid-secretion-predicted-by-a-computational-model-of-guinea-pig-pancreatic-duct-epithelium
#11
Makoto Yamaguchi, Martin C Steward, Kieran Smallbone, Yoshiro Sohma, Akiko Yamamoto, Shigeru B H Ko, Takaharu Kondo, Hiroshi Ishiguro
KEY POINTS: The ductal system of the pancreas secretes large volumes of alkaline fluid containing HCO3(-) concentrations as high as 140 mm during hormonal stimulation. A computational model has been constructed to explore the underlying ion transport mechanisms. Parameters were estimated by fitting the model to experimental data from guinea-pig pancreatic ducts. The model was readily able to secrete 140 mm HCO3(-) . Its capacity to do so was not dependent upon special properties of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channels and solute carrier family 26 member A6 (SLC26A6) anion exchangers...
December 20, 2016: Journal of Physiology
https://www.readbyqxmd.com/read/27939580/microrna-101-regulates-multiple-developmental-programs-to-constrain-excitation-in-adult-neural-networks
#12
Giordano Lippi, Catarina C Fernandes, Laura A Ewell, Danielle John, Benedetto Romoli, Giulia Curia, Seth R Taylor, E Paxon Frady, Anne B Jensen, Jerry C Liu, Melanie M Chaabane, Cherine Belal, Jason L Nathanson, Michele Zoli, Jill K Leutgeb, Giuseppe Biagini, Gene W Yeo, Darwin K Berg
A critical feature of neural networks is that they balance excitation and inhibition to prevent pathological dysfunction. How this is achieved is largely unknown, although deficits in the balance contribute to many neurological disorders. We show here that a microRNA (miR-101) is a key orchestrator of this essential feature, shaping the developing network to constrain excitation in the adult. Transient early blockade of miR-101 induces long-lasting hyper-excitability and persistent memory deficits. Using target site blockers in vivo, we identify multiple developmental programs regulated in parallel by miR-101 to achieve balanced networks...
December 21, 2016: Neuron
https://www.readbyqxmd.com/read/27926982/trpv4-channels-mediate-na-k-cl-co-transporter-induced-brain-edema-after-traumatic-brain-injury
#13
Kwok-Tung Lu, Tai-Chun Huang, Ya-Hsin Tsai, Yi-Ling Yang
Na(+) -K(+) -2Cl(-) co-transporter (NKCC1) plays an important role in traumatic brain injury (TBI)-induced brain edema via the mitogen-activated protein kinases (MAPK) cascade. The transient receptor potential vanilloid type 4 (TRPV4) channel participates in neurogenic inflammation, pain transmission and edema. In this study, we investigated the relationship between NKCC1 and TRPV4 and the related signaling pathways in TBI-induced brain edema and neuronal damage. TBI was induced by the calibrated weight-drop device...
December 7, 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27900370/a-patient-with-multisystem-dysfunction-carries-a-truncation-mutation-in-human-slc12a2-the-gene-encoding-the-na-k-2cl-cotransporter-nkcc1
#14
Eric Delpire, Lynne Wolfe, Bianca Flores, Rainelli Koumangoye, Cara C Schornak, Salma Omer, Barbara Pusey, Christopher Lau, Thomas Markello, David R Adams
This study describes a 13-yr-old girl with orthostatic intolerance, respiratory weakness, multiple endocrine abnormalities, pancreatic insufficiency, and multiorgan failure involving the gut and bladder. Exome sequencing revealed a de novo, loss-of-function allele in SLC12A2, the gene encoding the Na-K-2Cl cotransporter-1. The 11-bp deletion in exon 22 results in frameshift (p.Val1026Phefs*2) and truncation of the carboxy-terminal tail of the cotransporter. Preliminary studies in heterologous expression systems demonstrate that the mutation leads to a nonfunctional transporter, which is expressed and trafficked to the plasma membrane alongside wild-type NKCC1...
November 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27881573/intestinal-na-k-2cl-cotransporter-2-plays-a-crucial-role-in-hyperosmotic-transitions-of-a-euryhaline-teleost
#15
Andrew J Esbaugh, Brett Cutler
Euryhaline fishes, such as the red drum (Sciaenops ocellatus), must quickly transition between hyperosmotic and hypoosmotic physiological strategies. When freshwater individuals transition to seawater they are exposed to increased diffusive water loss and ion gain. To maintain osmoregulatory balance these animals must drink and absorb seawater through the intestine, followed by ion excretion at the gills. The ability of fishes to transition between strategies can limit the magnitude of osmotic shock that can be tolerated...
November 2016: Physiological Reports
https://www.readbyqxmd.com/read/27871891/long-term-alcohol-exposure-elicits-hippocampal-nonsynaptic-epileptiform-activity-changes-associated-with-expression-and-functional-changes-in-nkcc1-kcc2-co-transporters-and-na-k-atpase
#16
Luiz E C Santos, Antônio M Rodrigues, Mariana R Lopes, Victor D C Costa, Carla A Scorza, Fulvio A Scorza, Esper A Cavalheiro, Antônio-Carlos G Almeida
Nonsynaptic mechanism changes, particularly the enhancement of NKCC1 expression in the dentate gyrus (DG) after 4weeks of ethanol consumption, motivate the present work, in which rats were submitted to a period of chronic consumption (12weeks). Four groups of six animals (6-week-old male Wistar rats) were formed, including the control (C), ethanol 1 (E1), ethanol 2 (E2) and ethanol 3 (E3) groups. The rats in the E1, E2 and E3 groups were treated daily with a 30% v/v solution of ethanol, administered via oral gavage (1...
January 6, 2017: Neuroscience
https://www.readbyqxmd.com/read/27866192/dietary-genistein-rescues-reduced-basal-chloride-secretion-in-diabetic-jejunum-via-sex-dependent-mechanisms
#17
Shawn Catmull, Faisal Masood, Sydney Schacht, Robert Dolan, Daniel Stegman, Lana Leung, Layla Al-Nakkash
BACKGROUND/AIMS: The goal of this study was to determine the effect of dietary genistein (naturally occurring phytoestrogen) on jejunal secretory function in a clinically relevant model of diabetes and obesity, the leptin-defIcient ob/ob mouse. METHODS: We measured transepithelial short circuit current (Isc), across freshly isolated segments of jejunum from 12-week old male and female ob/ob and lean C57Bl/6J mice fed a genistein diet (600 mg genistein/kg diet) for 4-weeks...
2016: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/27861901/chloride-co-transporters-as-possible-therapeutic-targets-for-stroke
#18
REVIEW
Miguel A S Martín-Aragón Baudel, Amy V Poole, Mark G Darlison
Stroke is one of the major causes of death and disability worldwide. The major type of stroke is an ischaemic one, which is caused by a blockage that interrupts blood flow to the brain. There are currently very few pharmacological strategies to reduce the damage and social burden triggered by this pathology. The harm caused by the interruption of blood flow to the brain unfolds in the subsequent hours and days, so it is critical to identify new therapeutic targets that could reduce neuronal death associated with the spread of the damage...
November 15, 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27859594/glutamate-transporter-associated-anion-channels-adjust-intracellular-chloride-concentrations-during-glial-maturation
#19
Verena Untiet, Peter Kovermann, Niklas J Gerkau, Thomas Gensch, Christine R Rose, Christoph Fahlke
Astrocytic volume regulation and neurotransmitter uptake are critically dependent on the intracellular anion concentration, but little is known about the mechanisms controlling internal anion homeostasis in these cells. Here we used fluorescence lifetime imaging microscopy (FLIM) with the chloride-sensitive dye MQAE to measure intracellular chloride concentrations in murine Bergmann glial cells in acute cerebellar slices. We found Bergmann glial [Cl(-) ]int to be controlled by two opposing transport processes: chloride is actively accumulated by the Na(+) -K(+) -2Cl(-) cotransporter NKCC1, and chloride efflux through anion channels associated with excitatory amino acid transporters (EAATs) reduces [Cl(-) ]int to values that vary upon changes in expression levels or activity of these channels...
February 2017: Glia
https://www.readbyqxmd.com/read/27853306/osr1-and-spak-cooperatively-modulate-sertoli-cell-support-of-mouse-spermatogenesis
#20
Yung-Liang Liu, Sung-Sen Yang, Shyi-Jou Chen, Yu-Chun Lin, Chin-Chen Chu, Hsin-Hui Huang, Fung-Wei Chang, Mu-Hsien Yu, Shih-Hua Lin, Gwo-Jang Wu, Huey-Kang Sytwu
We investigated the role of oxidative stress-responsive kinase-1 (OSR1) and STE20 (sterile 20)/SPS1-related proline/alanine-rich kinase (SPAK), upstream regulators of the Na(+)-K(+)-2Cl(-) cotransporter (NKCC1)-essential for spermatogenesis-in mouse models of male fertility. Global OSR1(+/-) gene mutations, but not global SPAK(-/-) or Sertoli cell (SC)-specific OSR1 gene knockout (SC-OSR1(-/-)), cause subfertility with impaired sperm function and are associated with reduced abundance of phosphorylated (p)-NKCC1 but increased p-SPAK expression in testicular tissue and spermatozoa...
November 17, 2016: Scientific Reports
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