Discovery of a Small Molecule Drug Candidate for Selective NKCC1 Inhibition in Brain Disorders

Savardi, Annalisa; Borgogno, Marco; Narducci, Roberto; Sala, Giuseppina La; Ortega, J.A.; Summa, Maria; Armirotti, Andrea; Bertorelli, Rosalia; Contestabile, Andrea; Vivo, Marco De; Cancedda, Laura

doi:10.1016/j.chempr.2020.06.017

Cited by 51 publications

(112 citation statements)

References 58 publications

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“…[65] (polyclonal rabbit antibodies by Kurihara, 1999, Moore-Hoon and Turner, 1998, and Kaplan, 1996, (5), and (7), respectively). However, this staining pattern has been suggested to originate at least partially from satellite glia, which tightly surround the DRG neurons [66] (affinity-purified rabbit polyclonal antibodies by McDaniel and Lytle, 1999, andDel Castillo, 2005, antigens (1) and (4), respectively, and nucleotide (11) in Figure 2), ref. [67] (T4, antigen (6) in Figure 1).…”

Section: Nkcc1 Functions Outside the Cnsmentioning

confidence: 99%

“…During the second postnatal week in rats and mice [4] and around the time of full-term birth in humans [8,9], KCC2 is upregulated, leading to a decrease in neuronal intracellular chloride concentration ([Cl − ] i ) and a shift towards more hyperpolarizing GABAergic responses. NKCC1 is currently gaining increased attention as a possible therapeutic target for treating a myriad of CNS disorders [10], and the search for brain-permeable and specific NKCC1 drugs is heating up [11][12][13]. However, a major caveat here is that our understanding of the spatiotemporal expression patterns of NKCC1 in the brain is still in its infancy.…”

Section: Introductionmentioning

confidence: 99%

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NKCC1, an Elusive Molecular Target in Brain Development: Making Sense of the Existing Data

Virtanen

Uvarov

Hübner

et al. 2020

Cells

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Ionotropic GABA transmission is mediated by anion (mainly Cl−)-permeable GABAA receptors (GABAARs). In immature neurons, GABA exerts depolarizing and sometimes functionally excitatory actions, based on active uptake of Cl− by the Na-K-2Cl cotransporter NKCC1. While functional evidence firmly shows NKCC1-mediated ion transport in immature and diseased neurons, molecular detection of NKCC1 in the brain has turned out to be extremely difficult. In this review, we describe the highly inconsistent data that are available on the cell type-specific expression patterns of the NKCC1 mRNA and protein in the CNS. We discuss the major technical caveats, including a lack of knock-out-controlled immunohistochemistry in the forebrain, possible effects of alternative splicing on the binding of antibodies and RNA probes, and the wide expression of NKCC1 in different cell types, which make whole-tissue analyses of NKCC1 useless for studying its neuronal expression. We also review novel single-cell RNAseq data showing that most of the NKCC1 in the adult CNS may, in fact, be expressed in non-neuronal cells, especially in glia. As future directions, we suggest single-cell NKCC1 mRNA and protein analyses and the use of genetically tagged endogenous proteins or systematically designed novel antibodies, together with proper knock-out controls, for the visualization of endogenous NKCC1 in distinct brain cell types and their subcellular compartments.

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Section: Nkcc1 Functions Outside the Cnsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

NKCC1, an Elusive Molecular Target in Brain Development: Making Sense of the Existing Data

Virtanen

Uvarov

Hübner

et al. 2020

Cells

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“…39–43 Recently, Hampel et al described Azosemide as a more potent inhibitor of human NKCC1, 44 and Savardi et al identified a new compound, ARN23746, that modestly inhibits NKCC1 function (30% at 10 uM and 95% at 100 uM), but had no effect on NKCC2. 45 …”

Section: Pharmacologymentioning

confidence: 99%

NKCC1: Newly Found as a Human Disease-Causing Ion Transporter

2020

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SUMMARY Among the electroneutral Na+-dependent chloride transporters, NKCC1 had until now evaded identification as a protein causing human diseases. The closely related SLC12A transporters, NKCC2 and NCC have been identified some 25 years ago as responsible for Bartter and Gitelman syndromes: two renal-dependent salt wasting disorders. Absence of disease was most surprising since the NKCC1 knockout mouse was shown in 1999 to be viable, albeit with a wide range of deleterious phenotypes. Here we summarize the work of the past five years that introduced us to clinical cases involving NKCC1. The most striking cases are of 3 children with inherited mutations, who have complete absence of NKCC1 expression. These cases establish that lack of NKCC1 causes deafness; CFTR-like secretory defects with mucus accumulation in lung and intestine; severe xerostomia, hypotonia, dysmorphic facial features, and severe neurodevelopmental disorder. Another intriguing case is of a patient with a dominant deleterious SLC12A2 allele. This de novo mutation introduced a premature stop codon leading to a truncated protein. This mutant transporter seems to exert dominant-negative effect on wild-type transporter only in epithelial cells. The patient who suffers from lung, bladder, intestine, pancreas, and multiple endocrine abnormalities has, however, normal hearing and cognition. Finally, new reports substantiate the haploinsufficiency prediction of the SLC12A2 gene. Cases with single allele mutations in SLC12A2 have been linked to hearing loss and neurodevelopmental disorders.

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“…has now discovered a new drug candidate, termed ARN23746, which active selectively for NKCC1 in vivo versus NKCC2 [10].…”

Section: Nkcc In Vascular Cellsmentioning

confidence: 99%

Role of the Cation-chloride-cotransporters in Cardiovascular Disease

Azlan

Zhang

2020

Preprint

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The SLC12 family of cation-chloride-cotransporters (CCCs), comprising potassium chloride cotransporters (KCCs)-mediated Cl- extrusion relative to sodium chloride cotransporters (NKCCs)-mediated Cl- loading, play vital roles in cell volume regulation and ion homeostasis. These functions of the CCCs influence a variety of physiological processes, many of which overlap with the pathophysiology of cardiovascular disease. Although not all of the cotransporters have been linked to Mendelian genetic disorders, recent studies have provided new insights into their functional role in vascular and renal cells along with their contribution to cardiovascular diseases. Particularly, an imbalance in potassium levels promote the pathogenesis of atherosclerosis and disturbances in sodium homeostasis are one of the causes of hypertension. Recent findings even suggest hypothalamic signalling as a key signalling pathway in the pathophysiology of hypertension. In this review, we summarize and discuss the role of CCCs in cardiovascular disease with particular emphasis on knowledge gained in recent years on NKCCs and KCCs.

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Discovery of a Small Molecule Drug Candidate for Selective NKCC1 Inhibition in Brain Disorders

Cited by 51 publications

References 58 publications

NKCC1, an Elusive Molecular Target in Brain Development: Making Sense of the Existing Data

NKCC1, an Elusive Molecular Target in Brain Development: Making Sense of the Existing Data

NKCC1: Newly Found as a Human Disease-Causing Ion Transporter

Role of the Cation-chloride-cotransporters in Cardiovascular Disease

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