Repurposing the Dihydropyridine Calcium Channel Inhibitor Nicardipine as a Nav1.8 Inhibitor In Vivo for Pitt Hopkins Syndrome.

Pharmaceutical Research
Sean EkinsAudrey Davidow

Abstract

Individuals with the rare genetic disorder Pitt Hopkins Syndrome (PTHS) do not have sufficient expression of the transcription factor 4 (TCF4) which is located on chromosome 18. TCF4 is a basic helix-loop-helix E protein that is critical for the normal development of the nervous system and the brain in humans. PTHS patients lacking sufficient TCF4 frequently display gastrointestinal issues, intellectual disability and breathing problems. PTHS patients also commonly do not speak and display distinctive facial features and seizures. Recent research has proposed that decreased TCF4 expression can lead to the increased translation of the sodium channel Nav1.8. This in turn results in increased after-hyperpolarization as well as altered firing properties. We have recently identified through a drug repurposing screen an FDA approved dihydropyridine calcium antagonist nicardipine used to treat angina, which inhibited Nav1.8. We have now performed behavioral testing in groups of 10 male Tcf4(± ) PTHS mice dosing by oral gavage at 3 mg/kg once a day for 3 weeks using standard methods to assess sociability, nesting, fear conditioning, self-grooming, open field and test of force. Nicardipine returned this spectrum of behavioral deficits i...Continue Reading

References

Jun 30, 1987·The American Journal of Cardiology·R L Whiting
Oct 17, 1989·The American Journal of Cardiology·A D Michel, R L Whiting
Apr 13, 1999·Genomics·N W Plummer, M H Meisler
Apr 5, 2007·Nature Protocols·Robert M J Deacon
Mar 8, 2011·Drug Discovery Today·Sean EkinsJoel S Freundlich
Apr 19, 2011·European Journal of Pharmacology·Corbin BachmeierDaniel Paris
Sep 5, 2012·ChemMedChem·Antonio NardiAchim Kless
Apr 20, 2013·Current Medicinal Chemistry·Bence HegyiNorbert Szentandrássy
Mar 31, 2015·European Journal of Medicinal Chemistry·Daniel LängleDennis Schade
Dec 10, 2015·Channels·Sharan K BagalNigel A Swain
Dec 17, 2015·Pharmaceutical Research·Sean Ekins, Jill Wood
Apr 9, 2016·Journal of Basic and Clinical Pharmacy·Anroop B Nair, Shery Jacob
Jul 5, 2016·Behavioural Brain Research·Anna Maria TartaglioneGemma Calamandrei
Aug 30, 2016·Cell Reports·Andrew J KennedyJ David Sweatt
Sep 7, 2017·Current Medicinal Chemistry·Erica ValencicIrena Mlinaric-Rascan
Oct 22, 2017·Drug Discovery Today·Brian DelavanZhichao Liu
Dec 10, 2017·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Courtney ThaxtonBenjamin D Philpot
Jan 11, 2018·Journal of Child Neurology·Kimberly GoodspeedSailaja Golla
Jan 14, 2018·Drug Discovery Today·Nancy C BakerAlexander Tropsha
May 25, 2018·Neuropharmacology·Michael R TranfagliaPatricia Cogram
Jun 23, 2018·PloS One·Sophie CruxMario M Dorostkar
Oct 31, 2018·Journal of the International Neuropsychological Society : JINS·Alexander TanVeronica Bordes Edgar
Jan 25, 2019·Clinical Genetics·Marcella ZollinoRaoul C Hennekam
Mar 7, 2019·Metallomics : Integrated Biometal Science·Alex G DaleckiFrank Wolschendorf
Sep 20, 2019·Science Advances·Abolfazl Doostparast TorshiziKai Wang

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Methods Mentioned

BETA
exome sequencing
Genotyping

Software Mentioned

VersaDat
Prism

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