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<p>Parkinson’s disease (PD) is the second most prevalent neurological disorder without a clear etiology and specific cure. Microglia-mediated neuroinflammation plays a pivotal role in the pathogenesis and progression of PD, which is influenced by various factors and involves multiple signaling pathways. CT-011, synthesized by combining nitrone-tetramethyl pyrazine (TMP) and caffeic acid through an ester bond, has shown neuroprotection against ischemic stroke and glutamate-induced neuronal damage in animal models. The purpose of this study is to explore the impact of CT-011 on PD-related neuroinflammation and its potential in treating PD. Results showed that CT-011 significantly inhibited lipopolysaccharide (LPS)-induced release of pro-inflammatory cytokines and mediators in BV2 microglial cells. CT-011 also effectively mitigated LPS-induced mitochondrial membrane potential (MMP) reduction, mitochondrial and intracellular reactive oxygen species (ROS) production. Meanwhile, CT-011's anti-inflammatory effect was related to its inhibition of the TLR4-mediated MyD88/NF-B and PI3K-mediated AKT/GSK3β pathways. More significantly, CT-011 repressed the NLRP3 inflammasome activation. Additionally, CT-011 protected primary neurons against microglial-mediated neurotoxicity in vitro<i>,</i> and ameliorated dopaminergic neuronal damage in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice with a consistent anti-neuroinflammatory effect in vivo. These results demonstrate that CT-011 effectively inhibits microglia-mediated neuroinflammation and exerts neuroprotective effects on dopamine neurons, thus making it a promising therapeutic candidate for PD.</p>

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Tetramethylpyrazine-caffeic Acid Hybrid CT-011 Exerts Dopaminergic Neuroprotection Through Inhibiting Microglia-mediated Neuroinflammation

  • 期刊论文

  • 发表日期：

    2025年11月15日

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  • Min Xie,
  • Yu Cheng,
  • Lizhen Yang,
  • Zijin Lin,
  • Hao Shen,
  • Xinhua Zhou,
  • Zheng Liu,
  • Jieyu Xing,
  • Sigui Zhou,
  • Haiyun Chen

摘要

Parkinson’s disease (PD) is the second most prevalent neurological disorder without a clear etiology and specific cure. Microglia-mediated neuroinflammation plays a pivotal role in the pathogenesis and progression of PD, which is influenced by various factors and involves multiple signaling pathways. CT-011, synthesized by combining nitrone-tetramethyl pyrazine (TMP) and caffeic acid through an ester bond, has shown neuroprotection against ischemic stroke and glutamate-induced neuronal damage in animal models. The purpose of this study is to explore the impact of CT-011 on PD-related neuroinflammation and its potential in treating PD. Results showed that CT-011 significantly inhibited lipopolysaccharide (LPS)-induced release of pro-inflammatory cytokines and mediators in BV2 microglial cells. CT-011 also effectively mitigated LPS-induced mitochondrial membrane potential (MMP) reduction, mitochondrial and intracellular reactive oxygen species (ROS) production. Meanwhile, CT-011's anti-inflammatory effect was related to its inhibition of the TLR4-mediated MyD88/NF-B and PI3K-mediated AKT/GSK3β pathways. More significantly, CT-011 repressed the NLRP3 inflammasome activation. Additionally, CT-011 protected primary neurons against microglial-mediated neurotoxicity in vitro, and ameliorated dopaminergic neuronal damage in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice with a consistent anti-neuroinflammatory effect in vivo. These results demonstrate that CT-011 effectively inhibits microglia-mediated neuroinflammation and exerts neuroprotective effects on dopamine neurons, thus making it a promising therapeutic candidate for PD.