Aquaporins: relevance to cerebrospinal fluid physiology and therapeutic potential in hydrocephalus

The discovery of a family of membrane water channel proteins called aquaporins, and the finding that aquaporin 1 was located in the choroid plexus, has prompted interest in the role of aquaporins in cerebrospinal fluid (CSF) production and consequently hydrocephalus. While the role of aquaporin 1 in choroidal CSF production has been demonstrated, the relevance of aquaporin 1 to the pathophysiology of hydrocephalus remains debated. This has been further hampered by the lack of a non-toxic specific pharmacological blocking agent for aquaporin 1. In recent times aquaporin 4, the most abundant aquaporin within the brain itself, which has also been shown to have a role in brain water physiology and relevance to brain oedema in trauma and tumours, has become an alternative focus of attention for hydrocephalus research. This review summarises current knowledge and concepts in relation to aquaporins, specifically aquaporin 1 and 4, and hydrocephalus. It also examines the relevance of aquaporins as potential therapeutic targets in hydrocephalus and other CSF circulation disorders

Aquaporins: important but elusive drug targets.

The aquaporins (AQPs) are a family of small, integral membrane proteins that facilitate water transport across the plasma membranes of cells in response to osmotic gradients. Data from knockout mice support the involvement of AQPs in epithelial fluid secretion, cell migration, brain oedema and adipocyte metabolism, which suggests that modulation of AQP function or expression could have therapeutic potential in oedema, cancer, obesity, brain injury, glaucoma and several other conditions. Moreover, loss-of-function mutations in human AQPs cause congenital cataracts (AQP0) and nephrogenic diabetes insipidus (AQP2), and autoantibodies against AQP4 cause the autoimmune demyelinating disease neuromyelitis optica. Although some potential AQP modulators have been identified, challenges associated with the development of better modulators include the druggability of the target and the suitability of the assay methods used to identify modulators

Aquaporin water channels in the nervous system.

The aquaporins (AQPs) are plasma membrane water-transporting proteins. AQP4 is the principal member of this protein family in the CNS, where it is expressed in astrocytes and is involved in water movement, cell migration and neuroexcitation. AQP1 is expressed in the choroid plexus, where it facilitates cerebrospinal fluid secretion, and in dorsal root ganglion neurons, where it tunes pain perception. The AQPs are potential drug targets for several neurological conditions. Astrocytoma cells strongly express AQP4, which may facilitate their infiltration into the brain, and the neuroinflammatory disease neuromyelitis optica is caused by AQP4-specific autoantibodies that produce complement-mediated astrocytic damage

Réforme de l'ortograffe : encore un effort…

Aquaporin (AQP) water channels, essential for fluid homeostasis, are expressed in perivascular brain end-feet regions of astroglia (AQP4) and in choroid plexus (AQP1). At a high concentration, the loop diuretic bumetanide has been shown to reduce rat brain edema after ischemic stroke by blocking Na⁺-K⁺-2Cl⁻ cotransport. We hypothesized that an additional inhibition of AQP contributes to the protection. We show that osmotic water flux in AQP4-expressing Xenopus laevis oocytes is reduced by extracellular bumetanide (≥100 μM). The efficacy of block by bumetanide is increased by injection intracellularly. Forty-five synthesized bumetanide derivatives were tested on oocytes expressing human AQP1 and rat AQP4. Of these, one of the most effective was the 4-aminopyridine carboxamide analog, AqB013, which inhibits AQP1 and AQP4 (IC₅₀ ∼20 μM, applied extracellularly). The efficacy of block was enhanced by mutagenesis of intracellular AQP4 valine-189 to alanine (V189A, IC50 ∼8 μM), confirming the aquaporin as the molecular target of block. In silico docking of AqB013 supported an intracellular candidate binding site in rat AQP4 and suggested that the block involves occlusion of the AQP water pore at the cytoplasmic side. AqB013 at 2 μM had no effect, and 20 μM caused 20% block of human Na⁺-K⁺-2Cl⁻ cotransporter activity, in contrast to >90% block of the transporter by bumetanide. AqB013 did not affect X. laevis oocyte Cl- currents and did not alter rhythmic electrical conduction in an ex vivo gastric muscle preparation. The identification of AQP-selective pharmacological agents opens opportunities for breakthrough strategies in the treatment of edema and other fluid imbalance disorders.Elton Migliati, Nathalie Meurice, Pascale DuBois, Jennifer S. Fang, Suma Somasekharan, Elizabeth Beckett, Gary Flynn and Andrea J. Yoo

The tof-guard neuromuscular transmission monitor and its use in horses O monitor da transmissão neuromuscular "tof-guard" e seu uso em eqüinos

It has been emphasized in the human medical literature, that when using a neuromuscular blocking agent, it is of vital importance the monitoring of the neuromuscular block and that these agents should never be used without it. The purpose of this study was to evaluate the use of the neuromuscular transmission monitor TOF-Guard in horses. Twelve horses were randomly assigned whether to receive pancuronium or atracurium as the neuromuscular blocking agent. All horses were pre-medicated with romifidine, anaesthesia induced with diazepam and ketamine and maintenance with halothane. Abolition of spontaneous ventilation was accomplished by the administration of atracurium or pancuronium. The time from injection of the muscle relaxant agent to the onset of maximum block (T1=0), recovery of T1 to 25% and the recovery of TOF ratio to 0.7 were recorded, as was the time for recovery of T1 from 25 to 75%. It was concluded that it is very important the neuromuscular transmission monitoring during the use of a nondepolarizing neuromuscular blocking agent, since it provides a safer anaesthetic and surgical procedure with the use of adequate dosages and due to the impossibility of a superficialization of the neuromuscular blockade during a surgical procedure. The TOF-Guard showed to be a good option for neuromuscular monitoring in horses.<br>Quando da utilização de bloqueadores neuromusculares, já foi enfatizado na literatura médica humana, que é de vital imporância a monitoração do bloqueio neuromuscular e que estes agentes nunca devem ser utilizados sem a mesma. O objetivo deste estudo foi o de avaliar o uso do monitor da transmissão neuromuscular TOF-Guard em eqüinos. Para tanto, doze eqüinos foram separados aleatoriamente para receberem como bloqueadores neuromusculares o pancurônio ou o atracúrio. Todos os eqüinos foram pré-medicados com romifidina, induzidos com diazepam e quetamina e mantidos com halotano. Foi administrado o atracúrio ou o pancurônio, seguindo-se a apnéia e início da ventilação mecânica controlada. O tempo entre a administração do relaxante muscular e a obtenção de um bloqueio máximo (T1=0), o retorno do T1 para 25% e da razão do TOF para 0,7 e o tempo do retorno do T1 de 25 para 75% foram mensurados. Concluiu-se que é de grande importância a monitoração do bloqueio neuromuscular quando da utilização de um bloqueador neuromuscular não-despolarizante, uma vez que ela torna o ato anestésico e cirúrgico mais seguro, com a utilização de doses adequadas que inviabilizam a superficialização do bloqueio durante o procedimento cirúrgico. O monitor TOF-Guard mostrou ser uma boa opção para a monitoração do bloqueio neuromuscular em eqüinos

Aquaporins in Cerebrovascular Disease: A Target for Treatment of Brain Edema?

In cerebrovascular disease, edema formation is frequently observed within the first 7 days and is characterized by molecular and cellular changes in the neurovascular unit. The presence of water channels, aquaporins (AQPs), within the neurovascular unit has led to intensive research in understanding the underlying roles of each of the AQPs under normal conditions and in different diseases. In this review, we summarize some of the recent knowledge on AQPs, focusing on AQP4, the most abundant AQP in the central nervous system. Several experimental models illustrate that AQPs have dual, complex regulatory roles in edema formation and resolution. To date, no specific therapeutic agents have been developed to inhibit water flux through these channels. However, experimental results strongly suggest that this is an important area for future investigation. In fact, early inhibition of water channels may have positive effects in the prevention of edema formation. At later time points during the course of disease, AQP is important for the clearance of water from the brain into blood vessels. Thus, AQPs, and in particular AQP4, have important roles in the resolution of edema after brain injury. The function of these water channel proteins makes them an excellent therapeutic target

Discovery of novel human Aquaporin-1 Blockers

Human aquaporin-1 (hAQP1) is a water channel found in many tissues and potentially involved in several human pathologies. Selective inhibitors of hAQP1 are discussed as novel treatment opportunities for glaucoma, brain edema, inflammatory pain, and certain types of cancer. However, only very few potent and chemically attractive blockers have been reported to date. In this study we present three novel hAQP1 blockers that have been identified by virtual screening and inhibit water flux through hAQP1 in Xenopus laevis oocyte swelling assays at low micromolar concentrations. The newly discovered compounds display no chemical similarity to hitherto known hAQP1 blockers and bind at the extracellular entrance of the channel, close to the ar/R selectivity filter. Futhermore, mutagenesis studies showed that Lys36, which is not conserved among the hAQP family, is crucially involved in binding and renders the discovered compounds suitable as leads for the development of selective hAQP1 inhibitors. © 2012 American Chemical SocietyPeer Reviewe