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Inflachromene Blocks Neuronal HMGB1 Translocation to Mitigate Hippocampal TLR4-NF-κB-Mediated Neuroinflammation and
Wu Zhou1, Bo Hei2, Zhixin Liu3
1Jiangxi Key Laboratory of Neurological Diseases, Department of Neurosurgery, the 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, No. 17 Yongwaizheng Street, Nanchang, Jiangxi, 330006, China.
Spinal cord injury (SCI) can trigger depression by releasing neuronal High Mobility Group Box-1 (HMGB1), which activates microglial inflammation. The compound inflachromene (ICM) targets HMGB1 translocation, offering a potential treatment for SCI-induced depression.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Spinal cord injury (SCI) is increasingly linked to chronic brain damage, manifesting as depression and cognitive deficits.
- High Mobility Group Box-1 (HMGB1), a key factor in central nervous system disorders, is implicated in SCI-induced depression, but its precise role remains unclear.
- Understanding the HMGB1-mediated mechanisms is crucial for developing effective therapeutic strategies for SCI-related depression.
Purpose of the Study:
- To elucidate the mechanisms by which HMGB1 contributes to depression-like behaviors following SCI.
- To evaluate the therapeutic potential of inflachromene (ICM) in an established rat model of SCI-induced depression.
- To investigate the role of the HMGB1-TLR4-NF-κB signaling axis in SCI-induced neuroinflammation and depressive behaviors.
Main Methods:
- Established a rat model of SCI-induced depression, assessing neurobehavioral outcomes, microglial activation, and neuronal damage.
- Utilized molecular docking, hippocampal RNA-seq, immunofluorescence, Western blotting, qRT-PCR, and ELISA to analyze molecular pathways and treatment effects.
- Employed a microglia-neuron co-culture system to investigate the role of neuronal HMGB1 and the effects of ICM and siRNA knockdown.
Main Results:
- Inflachromene (ICM) significantly suppressed microglial activation and reduced hippocampal neuronal injury in the SCI model.
- ICM alleviated neuroinflammation by inhibiting HMGB1 nuclear translocation, thereby blocking the HMGB1-TLR4-NF-κB signaling pathway.
- Neuronal HMGB1 was identified as the upstream driver of TLR4-NF-κB-dependent neuroinflammation, leading to depressive-like behaviors.
Conclusions:
- Targeting HMGB1 nuclear translocation with ICM is a promising therapeutic strategy for depression following SCI.
- The HMGB1-TLR4-NF-κB axis is a critical inflammatory mechanism underlying SCI-induced depression.
- ICM effectively mitigates SCI-induced neuroinflammation and depressive behaviors by modulating HMGB1 signaling.
