ArticleNeurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics2021
Betulinic Acid Hydroxamate is Neuroprotective and Induces Protein Phosphatase 2A-Dependent HIF-1α Stabilization and Post-transcriptional Dephosphorylation of Prolyl Hydrolase 2.
Article in Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 21 citations in OpenAlex.
- Multitarget Actions of Pentacyclic Triterpenic Acids in Alzheimer's Disease: Mechanistic Insights.Molecules (Basel, Switzerland) · 2026Review
- Mechanistic Insights into the Metabolic Pathways and Neuroprotective Potential of Pentacyclic Triterpenoids: In-Depth Analysis of Betulin, Betulinic, and Ursolic Acids.Biomolecules · 2025Review
- Receptor-mediated mitophagy: a new target of neurodegenerative diseases.Frontiers in neurology · 2025Review
- Etrinabdione (VCE-004.8), a B55α activator, promotes angiogenesis and arteriogenesis in critical limb ischemia.Journal of translational medicine · 2024Article
- Uncovering the ferroptosis related mechanism of laduviglusib in the cell-type-specific targets of the striatum in Huntington's disease.BMC genomics · 2024Article
- Neuroprotective Efficacy of Betulinic Acid Hydroxamate, a B55α/PP2A Activator, in Acute Hypoxia-Ischemia-Induced Brain Damage in Newborn Rats.Translational stroke research · 2023Article
- Neuroprotective Effects of Betulinic Acid Hydroxamate in Intraventricular Hemorrhage-Induced Brain Damage in Immature Rats.Nutrients · 2022Article
- A cannabidiol aminoquinone derivative activates the PP2A/B55α/HIF pathway and shows protective effects in a murine model of traumatic brain injury.Journal of neuroinflammation · 2022Article
- Neuroinflammation in Huntington's disease: From animal models to clinical therapeutics.Frontiers in immunology · 2022Review
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Authors and funding
10 authors at 3 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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