ArticleCNS neuroscience & therapeutics2025
Netrin-1 Inhibits Neuroinflammation by Modulating DRD2/GSK3β Signaling and Suppressing ROS in a Parkinson's Disease Model.
Article in CNS neuroscience & therapeutics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- Netrin-1 Inhibits Neuroinflammation by Modulating DRD2/GSK3β Signaling and Suppressing ROS in a Parkinson's Disease Model.CNS neuroscience & therapeutics · 2025Article
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8 authors.
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Abstract
backgroundNetrin-1 is stably expressed in mature neurons, where it regulates synaptic plasticity, promotes neuronal survival, and modulates cell adhesion and migration. However, the molecular link between Netrin-1 and the pathogenesis of Parkinson's disease (PD) has not yet been clearly elucidated.
aimsIn this study, we investigated the neuroprotective effects of Netrin-1 against dopaminergic neuronal death associated with PD pathology.
resultsHere, we show that in a rotenone-induced cellular model, Netrin-1 treatment significantly reduced reactive oxygen species (ROS) production, α-synuclein phosphorylation, and subsequent apoptosis. Moreover, Netrin-1 suppressed the expression of pro-inflammatory cytokines, including IL-6, TNF-α, and IL-1β, and promoted the activation of dopamine D2 receptor (DRD2) signaling, which is crucial for dopaminergic neuron survival. Of note, in the Netrin-1 conditional knockout mouse model, we observed significant dopaminergic neuronal loss, accompanied by increased α-synuclein hyperphosphorylation at Ser129 and elevated levels of the truncated form of deleted in colorectal cancer (DCC) generated by activated caspase-3, a marked depletion of DRD2 expression, and hyperphosphorylation of GSK3β at Tyr216. In contrast, these pathological features were attenuated in Netrin-1 wild-type (WT) mice. Additionally, the aging process in α-synuclein (SNCA) transgenic (Tg) mice was characterized by reduced levels of Netrin-1 and DRD2, alongside increased α-synuclein accumulation, proinflammatory cytokines, and caspase-3 activation.
conclusionThese findings suggest that Netrin-1 protects dopaminergic neurons by regulating neuroinflammation, preserving DRD2 signaling, and inhibiting phosphorylation of GSK3β at Tyr216, thereby offering potential as a therapeutic agent for dopaminergic neurodegeneration.
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