Inhibition of Aquaporin-4 Improves the Outcome of Ischaemic Stroke and Modulates Brain Paravascular Drainage Pathways

Pirici, Ionica; Balsanu, Tudor Adrian; Cãtãlin, Bogdan; Mărgăritescu, Claudiu; Divan, Tamir; Văcăraș, Vitalie; Mogoantă, Laurențiu; Pirici, Daniel; Carare, Roxana O.; Mureșanu, Dafin F.

doi:10.3390/ijms19010046

Cited by 68 publications

(55 citation statements)

References 54 publications

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“…Furthermore, AZA treatment in the same mice caused a significant increase in blood flow in both wild type and knockout mice, confirming that AZA may not be mAQP4 specific, whereas a saline injection did not increase blood flow in either type of mouse [105]. A single dose of TGN-020 (intraperitoneal 100 mg/kg) administered 15 min post medial cerebral artery occlusion in a rat model of non-reperfusion ischemia significantly reduced edema size, glial scar, albumin effusion, and apoptosis, which were attributed to inhibition of rAQP4, although no rAQP4 knockout rat model was tested to confirm [106].…”

Section: Regulation Of Aqp4 Via Small Molecule Inhibitorsmentioning

confidence: 94%

Regulation of AQP4 in the Central Nervous System

Vandebroek

Yasui

2020

IJMS

106

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Aquaporin-4 (AQP4) is the main water channel protein expressed in the central nervous system (CNS). AQP4 is densely expressed in astrocyte end-feet, and is an important factor in CNS water and potassium homeostasis. Changes in AQP4 activity and expression have been implicated in several CNS disorders, including (but not limited to) epilepsy, edema, stroke, and glioblastoma. For this reason, many studies have been done to understand the various ways in which AQP4 is regulated endogenously, and could be regulated pharmaceutically. In particular, four regulatory methods have been thoroughly studied; regulation of gene expression via microRNAs, regulation of AQP4 channel gating/trafficking via phosphorylation, regulation of water permeability using heavy metal ions, and regulation of water permeability using small molecule inhibitors. A major challenge when studying AQP4 regulation is inter-method variability. A compound or phosphorylation which shows an inhibitory effect in vitro may show no effect in a different in vitro method, or even show an increase in AQP4 expression in vivo. Although a large amount of variability exists between in vitro methods, some microRNAs, heavy metal ions, and two small molecule inhibitors, acetazolamide and TGN-020, have shown promise in the field of AQP4 regulation.

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Section: Regulation Of Aqp4 Via Small Molecule Inhibitorsmentioning

confidence: 94%

Regulation of AQP4 in the Central Nervous System

Vandebroek

Yasui

2020

IJMS

106

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“…Authors proposed a mechanism involving the attenuation of p38-MAPK signaling (Cheng et al, 2018). Similarly, 2-(nicotinamide)-1,3,4thiadiazole (TGN-020) was shown to act as a potent AQP-4 inhibitor in a rodent model of ischemia (Pirici et al, 2018;Catalin et al, 2018). A Japanese herbal compound named Goreisan was able to reduce edema in an in vivo model of hypoxic-ischemic encephalopathy by reducing the lesioninduced upregulation of AQP-4 protein expression, and ameliorating the rat survival rate compared to the control group (Nakano et al, 2018).…”

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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“…A novel AQP4 inhibitor TGN-020 was later identified by Huber et al with an IC 50 of 3 μM. Administration of TGN-020, both pre- and post-MCAO, reduced cerebral edema, cortical infarction, gliosis, and albumin effusion in rodents [ 72 , 73 ]. Crystal structures of rAQP4 bound to AZA and TGN-020 have been revealed by in silico studies [ 68 , 74 ].…”

Section: Aquaporin (Aqp)mentioning

confidence: 99%

Drug development in targeting ion channels for brain edema

et al. 2020

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Cerebral edema is a pathological hallmark of various central nervous system (CNS) insults, including traumatic brain injury (TBI) and excitotoxic injury such as stroke. Due to the rigidity of the skull, edema-induced increase of intracranial fluid significantly complicates severe CNS injuries by raising intracranial pressure and compromising perfusion. Mortality due to cerebral edema is high. With mortality rates up to 80% in severe cases of stroke, it is the leading cause of death within the first week. Similarly, cerebral edema is devastating for patients of TBI, accounting for up to 50% mortality. Currently, the available treatments for cerebral edema include hypothermia, osmotherapy, and surgery. However, these treatments only address the symptoms and often elicit adverse side effects, potentially in part due to non-specificity. There is an urgent need to identify effective pharmacological treatments for cerebral edema. Currently, ion channels represent the third-largest target class for drug development, but their roles in cerebral edema remain ill-defined. The present review aims to provide an overview of the proposed roles of ion channels and transporters (including aquaporins, SUR1-TRPM4, chloride channels, glucose transporters, and proton-sensitive channels) in mediating cerebral edema in acute ischemic stroke and TBI. We also focus on the pharmacological inhibitors for each target and potential therapeutic strategies that may be further pursued for the treatment of cerebral edema.

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Inhibition of Aquaporin-4 Improves the Outcome of Ischaemic Stroke and Modulates Brain Paravascular Drainage Pathways

Cited by 68 publications

References 54 publications

Regulation of AQP4 in the Central Nervous System

Regulation of AQP4 in the Central Nervous System

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

Drug development in targeting ion channels for brain edema

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