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Updated: Feb 24, 2026
Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson's Disease
Published on: January 7, 2014
Oxymatrine-associated protection in an MPTP mouse model is accompanied by increased miR-141-3p and reduced HMGB1
1Department of Pharmacy, The Affiliated Taizhou Second People's Hospital of Yangzhou University, Taizhou, China.
Introduction:
Oxymatrine (OMT) alleviates damage to dopaminergic (DA) neurons and microglia-mediated neuroinflammation in an MPTP mouse model of parkinsonism by inhibiting the High-mobility group protein B1 (HMGB1) pathway. However, the precise mechanism by which OMT inhibits HMGB1 remains unclear. Although miR-141-3p is downregulated in the peripheral blood serum of Parkinson's disease (PD) patients, its potential relationship with HMGB1 remains unclear.
Methods:
TargetScan software and dual-luciferase reporter gene assays predicted that miR-141-3p binds to the 3'-UTR of HMGB1 mRNA. BV2 cells were transfected with miR-141-3p mimics and stimulated with MPP+ in vitro experiments. C57BL/6 J mice received stereotaxic injections of miR-141-3p agomir or miR-141-3p antagomir into the bilateral substantia nigra pars compacta (SNpc). Subsequently, the mice were intraperitoneally injected with MPTP four times within a single day. After miR-141-3p antagomir injection, OMT was administered continuously by injection for 7 days. Behavioral tests were assessed using the rotarod and open field tests. Real-time PCR, western blot, ELISA, and immunofluorescence staining were performed on BV2 cells and SNpc tissues.
Results:
Our study showed an inverse correlation between HMGB1 and miR-141-3p expression in both BV2 microglia exposed to MPP+ and MPTP-treated mice. TargetScan analysis identified complementary binding sites between miR-141-3p and the 3'-UTR of HMGB1 mRNA, which was subsequently confirmed through dual-luciferase reporter assays. Through experiments in BV2 microglia exposed to MPP+ and in MPTP-treated mice, miR-141-3p downregulates HMGB1, reduces pro-inflammatory cytokine readouts, and in vivo is associated with improved rotarod and open-field performance and attenuated Tyrosine Hydroxylase (TH)-positive neuronal loss. OMT increases miR-141-3p in the MPTP model, alongside reduced HMGB1 and inflammatory readouts, and these effects are diminished by miR-141-3p inhibition.
Conclusion:
miR-141-3p targets HMGB1 to inhibit microglial reaction and mitigate neuroinflammation both in vivo and vitro experiments, reduce TH-positive neuronal loss in the MPTP model. OMT increases miR-141-3p in the MPTP model, alongside reduced HMGB1 and inflammatory readouts, and these effects are diminished by miR-141-3p inhibition.
Insights
Oxymatrine (OMT) increases miR-141-3p, which targets HMGB1 to reduce neuroinflammation and dopaminergic neuron loss in Parkinson's disease models. Inhibiting miR-141-3p diminishes OMT's protective effects, revealing a key therapeutic mechanism.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Parkinson's disease (PD) involves dopaminergic neuron loss and neuroinflammation.
- Oxymatrine (OMT) shows neuroprotective effects in PD models by inhibiting High-mobility group protein B1 (HMGB1).
- The precise mechanism of OMT's HMGB1 inhibition and the role of miR-141-3p in PD are unclear.
Purpose of the Study:
- To investigate the mechanism by which OMT inhibits HMGB1 in Parkinson's disease models.
- To determine the role of miR-141-3p in regulating HMGB1 expression and neuroinflammation.
- To explore the therapeutic potential of targeting the miR-141-3p/HMGB1 pathway.
Main Methods:
- Bioinformatic prediction and dual-luciferase reporter assays confirmed miR-141-3p binding to HMGB1 3'-UTR.
- In vitro studies used BV2 microglia treated with MPP+ and transfected with miR-141-3p mimics.
- In vivo studies involved MPTP-treated mice receiving miR-141-3p agomir/antagomir and OMT treatment, followed by behavioral and molecular analyses.
Main Results:
- An inverse correlation between HMGB1 and miR-141-3p was observed in vitro and in vivo.
- miR-141-3p directly targets HMGB1, reducing pro-inflammatory cytokines and mitigating TH-positive neuronal loss.
- OMT treatment increased miR-141-3p levels, decreased HMGB1, and reduced inflammation, effects blunted by miR-141-3p inhibition.
Conclusions:
- miR-141-3p acts as a direct inhibitor of HMGB1, suppressing microglial activation and neuroinflammation.
- OMT exerts neuroprotection in Parkinson's models by upregulating miR-141-3p, which subsequently downregulates HMGB1.
- Targeting the miR-141-3p/HMGB1 axis represents a promising therapeutic strategy for Parkinson's disease.
