ArticleMolecular medicine (Cambridge, Mass.)2025
Coniferaldehyde reverses 3-nitropropionic acid-induced Huntington's disease pathologies via PKM2 restoration and JAK2/STAT3 inhibition.
Article in Molecular medicine (Cambridge, Mass.), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Sinomenine Liposomes Alleviate Neuropathic Pain in a Spared Nerve Injury Model by Regulating Astrocyte Reactivity Associated with Inhibition of the JAK2/STAT3 Pathway.Neurochemical research · 2026Article
- Upregulated PKM2 Protects Dopaminergic Neurons From Oxidative Damage Through Nrf2 Transactivation in an MPTP-Induced Mouse Model of Parkinson's Disease.CNS neuroscience & therapeutics · 2026Article
- Epidermal growth factor receptor modulation for neural repair: Implications for neurodegenerative disease therapy.Frontiers in molecular neuroscience · 2026Review
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4 authors.
Funding
Abstract
backgroundHuntington's disease (HD) is a fatal neurodegenerative disorder characterized by progressive motor decline and neuronal loss, with no curative disease-modifying therapies available. The mitochondrial toxin 3-nitropropionic acid (3-NP) is widely used to model HD-like pathologies. We investigated the therapeutic potential of coniferaldehyde (CFA), a natural phenolic compound with anti-inflammatory, antioxidant, and anti-radical properties, against 3-NP-induced neurodegeneration. Given the roles of oxidative stress, metabolic dysfunction, and neuroinflammation in HD, we hypothesize that CFA exerts neuroprotection by attenuating these processes via the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway - a novel target for CFA in HD.
methodsNeurological and behavioral deficits were assessed via neurological assessment scaling, rotarod, and open field tests. Nissl staining was performed to evaluate neuronal damage in the motor cortex and striatum. Dihydroethidium staining (DHE) was used to measure reactive oxygen species (ROS) levels, and the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay was conducted to detect apoptosis. Western blot assay and immunofluorescence staining were used to examine CFA's effect. Additionally, molecular docking was performed to analyze CFA's interaction with STAT3.
resultsCFA treatment significantly improved motor function, preserved neuronal architecture, and reduced apoptosis, as confirmed by Nissl and TUNEL staining. CFA also decreased ROS levels and restored pyruvate kinase M2 (PKM2) expression, a key regulator of metabolic homeostasis. Consistently, CFA attenuated neuroinflammation by suppressing Glial Fibrillary Acidic Protein (GFAP) expression and proinflammatory cytokines Interleukin-6 (IL-6) and Interleukin-1 beta (IL-1β). Molecular docking studies revealed a strong binding affinity between CFA and STAT3, and western blot analysis showed reduced phosphorylation of STAT3, indicating modulation of the JAK2/STAT3 signaling pathway.
conclusionThese findings demonstrate that CFA modulates oxidative, PKM2-mediated metabolic, and inflammatory pathways through the JAK2/STAT3 axis, enhancing motor function and neuronal survival in a 3-NP model of HD. This multi-targeted mechanism highlights its potential as a disease-modifying therapy for advancing therapeutic strategies in HD and related neurodegenerative disorders.
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