Guanabenz ameliorates disease in vanishing white matter mice in contrast to sephin1.
Journal
Annals of clinical and translational neurology
ISSN: 2328-9503
Titre abrégé: Ann Clin Transl Neurol
Pays: United States
ID NLM: 101623278
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
revised:
02
06
2022
received:
23
03
2022
accepted:
03
06
2022
pubmed:
3
7
2022
medline:
18
8
2022
entrez:
2
7
2022
Statut:
ppublish
Résumé
Vanishing white matter (VWM) is a leukodystrophy, characterized by stress-sensitive neurological deterioration and premature death. It is currently without curative treatment. It is caused by bi-allelic pathogenic variants in the genes encoding eukaryotic initiation factor 2B (eIF2B). eIF2B is essential for the regulation of the integrated stress response (ISR), a physiological response to cellular stress. Preclinical studies on VWM mouse models revealed that deregulated ISR is key in the pathophysiology of VWM and an effective treatment target. Guanabenz, an α2-adrenergic agonist, attenuates the ISR and has beneficial effects on VWM neuropathology. The current study aimed at elucidating guanabenz's disease-modifying potential and mechanism of action in VWM mice. Sephin1, an ISR-modulating guanabenz analog without α2-adrenergic agonistic properties, was included to separate effects on the ISR from α2-adrenergic effects. Wild-type and VWM mice were subjected to placebo, guanabenz or sephin1 treatments. Effects on clinical signs, neuropathology, and ISR deregulation were determined. Guanabenz's and sephin1's ISR-modifying effects were tested in cultured cells that expressed or lacked the α2-adrenergic receptor. Guanabenz improved clinical signs, neuropathological hallmarks, and ISR regulation in VWM mice, but sephin1 did not. Guanabenz's effects on the ISR in VWM mice were not replicated in cell cultures and the contribution of α2-adrenergic effects on the deregulated ISR could therefore not be assessed. Guanabenz proved itself as a viable treatment option for VWM. The exact mechanism through which guanabenz exerts its ameliorating impact on VWM requires further studies. Sephin1 is not simply a guanabenz replacement without α2-adrenergic effects.
Identifiants
pubmed: 35778832
doi: 10.1002/acn3.51611
pmc: PMC9380178
doi:
Substances chimiques
Adrenergic Agents
0
Eukaryotic Initiation Factor-2B
0
sephin1
9M998304JB
Guanabenz
GGD30112WC
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1147-1162Informations de copyright
© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
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