Betulinic Acid Hydroxamate is Neuroprotective and Induces Protein Phosphatase 2A-Dependent HIF-1α Stabilization and Post-transcriptional Dephosphorylation of Prolyl Hydrolase 2.
Animals
Corpus Striatum
/ drug effects
HEK293 Cells
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
/ metabolism
Hypoxia-Inducible Factor-Proline Dioxygenases
/ metabolism
Mice
Mice, Inbred C57BL
NIH 3T3 Cells
Neuroprotective Agents
/ pharmacology
Nitro Compounds
/ toxicity
Pentacyclic Triterpenes
/ pharmacology
Phosphorylation
/ drug effects
Propionates
/ toxicity
Protein Phosphatase 2
/ metabolism
Betulinic Acid
Betulinic acid
Hypoxia-inducing factor
Neuroprotection
Prolyl-hydroxylases
Protein phosphatase A2
Journal
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
ISSN: 1878-7479
Titre abrégé: Neurotherapeutics
Pays: United States
ID NLM: 101290381
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
accepted:
07
07
2021
pubmed:
3
8
2021
medline:
4
3
2022
entrez:
2
8
2021
Statut:
ppublish
Résumé
Huntington's disease (HD) is a neurodegenerative disorder characterized by unwanted choreatic movements, behavioral and psychiatric disturbances, and dementia. The activation of the hypoxic response pathway through the pharmacological inhibition of hypoxia-inducing factor (HIF) prolyl-hydroxylases (PHDs) is a promising approach for neurodegenerative diseases, including HD. Herein, we have studied the mechanism of action of the compound Betulinic acid hydroxamate (BAH), a hypoximimetic derivative of betulinic acid, and its efficacy against striatal neurodegeneration using complementary approaches. Firstly, we showed the molecular mechanisms through which BAH modifies the activity of the PHD2 prolyl hydroxylase, thus directly affecting HIF-1α stability. BAH treatment reduces PHD2 phosphorylation on Ser-125 residue, responsible for the control of its hydrolase activity. HIF activation by BAH is inhibited by okadaic acid and LB-100 indicating that a protein phosphatase 2A (PP2A) is implicated in the mechanism of action of BAH. Furthermore, in striatal cells bearing a mutated form of the huntingtin protein, BAH stabilized HIF-1α protein, induced Vegf and Bnip3 gene expression and protected against mitochondrial toxin-induced cytotoxicity. Pharmacokinetic analyses showed that BAH has a good brain penetrability and experiments performed in a mouse model of striatal neurodegeneration induced by 3-nitropropionic acid showed that BAH improved the clinical symptoms. In addition, BAH also prevented neuronal loss, decreased reactive astrogliosis and microglial activation, inhibited the upregulation of proinflammatory markers, and improved antioxidant defenses in the brain. Taken together, our results show BAH's ability to activate the PP2A/PHD2/HIF pathway, which may have important implications in the treatment of HD and perhaps other neurodegenerative diseases.
Identifiants
pubmed: 34339019
doi: 10.1007/s13311-021-01089-4
pii: 10.1007/s13311-021-01089-4
pmc: PMC8608974
doi:
Substances chimiques
Hif1a protein, mouse
0
Hypoxia-Inducible Factor 1, alpha Subunit
0
Neuroprotective Agents
0
Nitro Compounds
0
Pentacyclic Triterpenes
0
Propionates
0
Egln1 protein, mouse
EC 1.14.11.29
Hypoxia-Inducible Factor-Proline Dioxygenases
EC 1.14.11.29
Protein Phosphatase 2
EC 3.1.3.16
3-nitropropionic acid
QY4L0FOX0D
Betulinic Acid
4G6A18707N
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1849-1861Informations de copyright
© 2021. The Author(s).
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