Inhibition of Aquaporin 4 by antiepileptic drugs

Huber, Vincent J.; Teräs, Mika; Kwee, Ingrid L.; Nakada, Tsutomu

doi:10.1016/j.bmc.2007.12.038

Cited by 124 publications

(105 citation statements)

References 29 publications

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“…Recently, three papers from one laboratory reported AQP4 inhibition by a series of arylsulfonamides, antiepileptic drugs, and related molecules, with strong inhibition at low micromolar concentrations [8][9][10] . The rationale for their investigation of arylsulfonamides, such as acetazolamide, was reports suggesting acetazolamide inhibition of a different water channel, AQP1 [11][12][13] .…”

Section: Introductionmentioning

confidence: 99%

“…However, subsequent measurements in multiple systems in our laboratory 14 and others 15 showed that arylsulfonamides do not inhibit AQP1 water transport. The rationale for their investigation of antiepileptics was structural similarity of some antiepileptics to the arylsulfonamides and the speculation that antiepileptics may exert their effect, in part, by AQP4 water transport inhibition 10 . However, as mentioned above, AQP4 inhibition would likely worsen rather than prevent seizures.…”

Section: Introductionmentioning

confidence: 99%

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Lack of aquaporin-4 water transport inhibition by antiepileptics and arylsulfonamides

Yang

Zhang

Verkman

2008

Bioorganic & Medicinal Chemistry

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Inhibitors of brain glial water channel aquaporin-4 (AQP4) are of potential clinical utility, as they are predicted to modulate brain edema, neuroexcitation and glial scarring. Recently, Huber et al. (Bioorgan. Med. Chem. 2007, 17:1270 2008, in press) reported that a series of arylsulfomamides, antiepileptics, and related small molecules strongly inhibited AQP4 water transport with IC50s down to 1 μM. We retested the compounds with greatest reported potencies, including acetylsulfanilamide, acetazolamide, 6-ethoxy-benzothiazole-2-sulfonamide, topiramate, zonisamide, phenytoin, lamotrigine and sumatriptan, in AQP4-transfected mammalian cells and primary cultures of brain glial cells, using several sensitive assays of osmotic water permeability. Contrary to the findings of Huber et al., in our studies we found no significant inhibition of AQP4 water permeability by any of the compounds at concentrations up to 100 μM.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lack of aquaporin-4 water transport inhibition by antiepileptics and arylsulfonamides

Yang

Zhang

Verkman

2008

Bioorganic & Medicinal Chemistry

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“…Because of its role, inhibitors of AQP4 are sought, although so far with conflicting results. Certain quaternary ammonium compounds (6), antiepileptic drugs (7,8), and serotonin receptor agonists (9) have been reported to inhibit AQP4 water transport in oocytes with IC 50 values down to the low micromolar range. However, Yang et al (10) report no inhibition up to 100 M using different assay methods.…”

Section: T He Aquaporin (Aqp) Family Includes Both Aqps That Conductmentioning

confidence: 99%

Crystal structure of human aquaporin 4 at 1.8 Å and its mechanism of conductance

Yeh

Sandstrom

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

305

291

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Aquaporin (AQP) 4 is the predominant water channel in the mammalian brain, abundantly expressed in the blood-brain and braincerebrospinal fluid interfaces of glial cells. Its function in cerebral water balance has implications in neuropathological disorders, including brain edema, stroke, and head injuries. The 1.8-Å crystal structure reveals the molecular basis for the water selectivity of the channel. Unlike the case in the structures of water-selective AQPs AqpZ and AQP1, the asparagines of the 2 Asn-Pro-Ala motifs do not hydrogen bond to the same water molecule; instead, they bond to 2 different water molecules in the center of the channel. Molecular dynamics simulations were performed to ask how this observation bears on the proposed mechanisms for how AQPs remain totally insulating to any proton conductance while maintaining a single file of hydrogen bonded water molecules throughout the channel.brain edema ͉ inhibitor discovery ͉ NPA motif

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“…7 As a proof of concept, induction of AQP1 transcription in endothelial cells by corticosteroids is associated with an increase in water transport in vivo. 8 Antagonists for AQP1 and AQP4 have been developed, with a focus on arylsulfonamide compounds, including acetazolamide, 9 antiepileptic agents, 10 and derivatives of the loop diuretic bumetanide. 11 However, the effectiveness of acetazolamide and antiepileptics as AQP blockers has been disputed.…”

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confidence: 99%

AqF026 Is a Pharmacologic Agonist of the Water Channel Aquaporin-1

Yool¹,

Morelle

Cnops

et al. 2013

Journal of the American Society of Nephrology

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Aquaporin-1 (AQP1) facilitates the osmotic transport of water across the capillary endothelium, among other cell types, and thereby has a substantial role in ultrafiltration during peritoneal dialysis. At present, pharmacologic agents that enhance AQP1-mediated water transport, which would be expected to increase the efficiency of peritoneal dialysis, are not available. Here, we describe AqF026, an aquaporin agonist that is a chemical derivative of the arylsulfonamide compound furosemide. In the Xenopus laevis oocyte system, extracellular AqF026 potentiated the channel activity of human AQP1 by .20% but had no effect on channel activity of AQP4. We found that the intracellular binding site for AQP1 involves loop D, a region associated with channel gating. In a mouse model of peritoneal dialysis, AqF026 enhanced the osmotic transport of water across the peritoneal membrane but did not affect the osmotic gradient, the transport of small solutes, or the localization and expression of AQP1 on the plasma membrane. Furthermore, AqF026 did not potentiate water transport in Aqp1-null mice, suggesting that indirect mechanisms involving other channels or transporters were unlikely. Last, in a mouse gastric antrum preparation, AqF026 did not affect the Na-K-Cl cotransporter NKCC1. In summary, AqF026 directly and specifically potentiates AQP1-mediated water transport, suggesting that it deserves additional investigation for applications such as peritoneal dialysis or clinical situations associated with defective water handling.

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Inhibition of Aquaporin 4 by antiepileptic drugs

Cited by 124 publications

References 29 publications

Lack of aquaporin-4 water transport inhibition by antiepileptics and arylsulfonamides

Lack of aquaporin-4 water transport inhibition by antiepileptics and arylsulfonamides

Crystal structure of human aquaporin 4 at 1.8 Å and its mechanism of conductance

AqF026 Is a Pharmacologic Agonist of the Water Channel Aquaporin-1

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