CHIR99021 causes inactivation of Tyrosine Hydroxylase and depletion of dopamine in rat brain striatum
Hamdon, Sally (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Fernandez-Gonzalez, Pol (Universitat Autònoma de Barcelona)
Omar, Muhammad Yusof (Universitat Autònoma de Barcelona)
González Sepúlveda, Marta (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Ortiz de Pablo, Jordi (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Gil, Carles (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Universitat Autònoma de Barcelona. Institut de Neurociències

Fecha:	2024
Descripción:	11 pàg. 5293939 pàg.
Resumen:	CHIR99021, also known as laduviglusib or CT99021, is a Glycogen-synthase kinase 3β (GSK3β) inhibitor, which has been reported as a promising drug for cardiomyocyte regeneration or treatment of sensorial hearing loss. Since the activation of dopamine (DA) receptors regulates dopamine synthesis and they can signal through the β-arrestin pathway and GSK3β, we decided to check the effect of GSK3β inhibitors (CHIR99021, SB216763 and lithium ion) on the control of DA synthesis. Using ex vivo experiments with minces from rat brain striatum, we observed that CHIR99021, but not SB216763 or lithium, causes complete abrogation of both DA synthesis and accumulation, pointing to off-target effects of CHIR99021. This decrease can be attributed to tyrosine hydroxylase (TH) inhibition since the accumulation of L-DOPA in the presence of a DOPA decarboxylase inhibitor was similarly decreased. On the other hand, CHIR99021 caused a dramatic increase in the DOPAC/DA ratio, an indicator of DA metabolization, and hindered DA incorporation into striatum tissue. Tetrabenazine, an inhibitor of DA vesicular transport, also caused DA depletion and DOPAC/DA ratio increase to the same extent as CHIR99021. In addition, both CHIR99021 or SB216763, but not lithium, decreased TH phosphorylation in Ser19, but not in Ser31 or Ser40. These results demonstrate that CHIR99021 can lead to TH inactivation and DA depletion in brain striatum, opening the possibility of its use in DA-related disorders, and shows effects to be considered in future clinical trials. More work is needed to find the mechanism exerted by CHIR99021 on DA accumulation.
Ayudas:	Agencia Estatal de Investigación SAF2017-87199-R
Nota:	Altres ajuts: acords transformatius de la UAB
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	CHIR99021 ; Dopamine ; GSK3 ; HPLC ; Striatum ; Tyrosine Hydroxylase
Publicado en:	Neuropharmacology, Vol. 242 (2024) , p. 109759, ISSN 1873-7064

DOI: 10.1016/j.neuropharm.2023.109759
PMID: 37844866

11 p, 5.0 MB

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