Functionalized Phenylbenzamides Inhibit Aquaporin-4 Reducing Cerebral Edema and Improving Outcome in Two Models of CNS Injury

Farr, George W.; Hall, Christopher; Farr, Susan M.; Wade, Ramon; Detzel, Joshua M.; Adams, Amielia G.; Buch, Jasen M.; Beahm, Derek L.; Flask, Chris A.; Xu, Kui; LaManna, Joseph C.; McGuirk, Paul R.; Boron, Walter F.; Pelletier, Marc F.

doi:10.1016/j.neuroscience.2019.01.034

Cited by 44 publications

(40 citation statements)

References 72 publications

(76 reference statements)

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“…New AQP-4 partial antagonists have been discovered by library screening by Aeromics, Inc. (OH, USA). The drug AER-270, and its prodrug with enhanced solubility AER-271, have shown beneficial results on brain edema in two different model of cerebral injury in rats, reducing swelling and behavioral neurological damage (Farr et al, 2019). Since AQP-4 was found up-regulated in the aging brain, and mislocalized in AD, it would be interesting to test the hypothesis that treatment with AQP-4 modulator may slower brain senescence process and prevent neurological deficit through a fine regulation of this water channel.…”

Section: Pharmacological Tools Targeting Aqp-4mentioning

confidence: 99%

Altered Waste Disposal System in Aging and Alzheimer’s Disease: Focus on Astrocytic Aquaporin-4

et al. 2020

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Among the diverse cell types included in the general population named glia, astrocytes emerge as being the focus of a growing body of research aimed at characterizing their heterogeneous and complex functions. Alterations of both their morphology and activities have been linked to a variety of neurological diseases. One crucial physiological need satisfied by astrocytes is the cleansing of the cerebral tissue from waste molecules. Several data demonstrate that aquaporin-4 (AQP-4), a protein expressed by astrocytes, is crucially important for facilitating the removal of waste products from the brain. Aquaporins are water channels found in all district of the human organism and the most abundant isoform in the brain is AQP-4. This protein is involved in a myriad of astrocytic activities, including calcium signal transduction, potassium buffering, synaptic plasticity, astrocyte migration, glial scar formation and neuroinflammation. The highest density of AQP-4 is found at the astrocytic domains closest to blood vessels, the endfeet that envelop brain vessels, with low to zero expression in other astrocytic membrane regions. Increased AQP-4 expression and loss of polarization have recently been documented in altered physiological conditions. Here we review the latest findings related to aging and Alzheimer's disease (AD) on this topic, as well as the available knowledge on pharmacological tools to target AQP-4.

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Section: Pharmacological Tools Targeting Aqp-4mentioning

confidence: 99%

Altered Waste Disposal System in Aging and Alzheimer’s Disease: Focus on Astrocytic Aquaporin-4

et al. 2020

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“…The short duration of the severe model hampers the use of hard endpoints (e.g. survival) in studies of pharmacological intervention of elevated icP, since the mice may die even before the test substances are cleared from circulation [11]. in future investigations, the mouse model of mild Wi could be used for even longer studies than 90 min and may even, as the severe model has been [25], be performed without anesthesia to quantify neurological functionality and vascular cerebral effects during elevations of ICP.…”

Section: Severe Wi Induces Hypo-or Euvolemic Hn While Mild Wi Inducementioning

confidence: 99%

A new experimental mouse model of water intoxication with sustained increased intracranial pressure and mild hyponatremia without side effects of antidiuretics

et al. 2020

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The most used experimental mouse model of hyponatremia and elevated intracranial pressure (ICP) is intraperitoneal injection of water in combination with antidiuretics. This model of water intoxication (WI) results in extreme pathological changes and death within 1 h. To improve preclinical studies of the pathophysiology of elevated ICP, we characterized diuresis, cardiovascular parameters, blood ionogram and effects of antidiuretics in this model. We subsequently developed a new mouse model with mild hyponatremia and sustained increased ICP. To investigate the classical protocol (severe WI), C57BL/6mice were anesthetized and received an intraperitoneal injection of 20% body weight of MilliQ water with or without 0.4 µg•kg −1 desmopressin acetate (dDAVP). Corresponding Sham groups were also studied. In the new WI protocol (mild WI), 10% body weight of a solution containing 6.5 mM NaHCO 3 , 1.125 mM KCl and 29.75 mM NaCl was intraperitoneally injected. By severe WI, ICP and mean arterial pressure increased until brain stem herniation occurred (23 ± 3 min after injection). The cardiovascular effects were accelerated by dDAVP. Severe WI induced a halt to urine production irrespective of the use of dDAVP. Following the new mild WI protocol, ICP also increased but was sustained at a pathologically high level without inducing herniation. Mean arterial pressure and urine production were not affected during mild WI. In conclusion, the new mild WI protocol is a superior experimental model to study the pathophysiological effects of elevated ICP induced by water intoxication.

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“…Several attempts have been made to develop pharmacological inhibitors of AQP4 to reduce brain oedema following ischaemia with little success [151]. Recently, Far et al [152] have shown the effectiveness of two promising AQP4 inhibitors following a high throughput screening of small molecule libraries. AER-270 and AER-271 prevented oedema in a mouse model of water intoxication and in rodent models of MCAo respectively.…”

Section: Reviewmentioning

confidence: 99%

Cerebrospinal fluid dynamics and intracranial pressure elevation in neurological diseases

Bothwell

Janigro

Patabendige

2019

Fluids Barriers CNS

179

181

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The fine balance between the secretion, composition, volume and turnover of cerebrospinal fluid (CSF) is strictly regulated. However, during certain neurological diseases, this balance can be disrupted. A significant disruption to the normal CSF circulation can be life threatening, leading to increased intracranial pressure (ICP), and is implicated in hydrocephalus, idiopathic intracranial hypertension, brain trauma, brain tumours and stroke. Yet, the exact cellular, molecular and physiological mechanisms that contribute to altered hydrodynamic pathways in these diseases are poorly defined or hotly debated. The traditional views and concepts of CSF secretion, flow and drainage have been challenged, also due to recent findings suggesting more complex mechanisms of brain fluid dynamics than previously proposed. This review evaluates and summarises current hypotheses of CSF dynamics and presents evidence for the role of impaired CSF dynamics in elevated ICP, alongside discussion of the proteins that are potentially involved in altered CSF physiology during neurological disease. Undoubtedly CSF secretion, absorption and drainage are important aspects of brain fluid homeostasis in maintaining a stable ICP. Traditionally, pharmacological interventions or CSF drainage have been used to reduce ICP elevation due to over production of CSF. However, these drugs are used only as a temporary solution due to their undesirable side effects. Emerging evidence suggests that pharmacological targeting of aquaporins, transient receptor potential vanilloid type 4 (TRPV4), and the Na + –K + –2Cl − cotransporter (NKCC1) merit further investigation as potential targets in neurological diseases involving impaired brain fluid dynamics and elevated ICP.

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Functionalized Phenylbenzamides Inhibit Aquaporin-4 Reducing Cerebral Edema and Improving Outcome in Two Models of CNS Injury

Cited by 44 publications

References 72 publications

Altered Waste Disposal System in Aging and Alzheimer’s Disease: Focus on Astrocytic Aquaporin-4

Altered Waste Disposal System in Aging and Alzheimer’s Disease: Focus on Astrocytic Aquaporin-4

A new experimental mouse model of water intoxication with sustained increased intracranial pressure and mild hyponatremia without side effects of antidiuretics

Cerebrospinal fluid dynamics and intracranial pressure elevation in neurological diseases

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