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Histone Deacetylase 3 Inhibition Ameliorates Microglia-Mediated Neuro-Inflammation Via the SIRT1/Nrf2 Pathway After
Shoubo Chen1, Jingfang Ye2, Guozhong Wu1
1Department of Orthopaedics, The Second Affiliated Hospital, Fujian Medical University, Quanzhou, Fujian Province, China.
Background:
Microglial-induced inflammation plays a crucial role in the pathophysiological process of nervous system injury, however, still lacks effective therapeutic agents. Previously, we discovered that the inhibition of histone deacetylase 3 (HDAC3) exerts anti-inflammatory effects after traumatic spinal cord injury (SCI), whereas little is known about its underlying mechanism. Therefore, the present study aimed to explore the effects and potential mechanisms of HDAC3 on neuroinflammation and microglial function.
Methods:
Rats were randomized into 4 groups: sham group, SCI group, SCI + vehicle group, and SCI + RGF966 group. To examine the effect of HDAC3 on neurological deficit after SCI, we gathered data using the Basso Beattie Bresnahan locomotion scale, the inclined plane test, the blood-spinal cord barrier, junction protein expression, and Nissl staining. We also evaluated microglial activation and inflammatory factor levels. Immunofluorescence analysis, immunohistochemical analysis, western blotting, and quantitative real-time polymerase chain reaction were performed to examine the regulation of the Sirtuin 1 (SIRT1)/nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway.
Results:
The results showed that HDAC3 inhibition significantly ameliorated Basso-Beattie-Bresnahan (BBB) permeability, brain edema, and improved neurological functions and junction protein levels. Additionally, HDAC3 inhibition significantly inhibited microglial activation, thereby reducing the levels of SCI-induced pro-inflammatory factors. Moreover, HDAC3 inhibition dramatically enhanced the expression of SIRT1 and increased both Nrf2 nuclear accumulation and transcriptional activity, thereby increasing downstream heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1 expression.
Conclusions:
The results of this study suggest that HDAC3 inhibition protects the spinal cord from injury following SCI by inhibiting SCI-induced microglial activation and the subsequent inflammatory response via SIRT1/Nrf2 signaling pathway, highlighting HDAC3 as a potential therapeutic target for the treatment of SCI.
Insights
Inhibiting histone deacetylase 3 (HDAC3) reduces spinal cord injury inflammation by calming microglial activation. This neuroprotective effect is mediated by the SIRT1/Nrf2 pathway, suggesting HDAC3 as a therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Microglial-induced inflammation is a key factor in nervous system injury, yet effective treatments are limited.
- Histone deacetylase 3 (HDAC3) inhibition shows anti-inflammatory effects post-spinal cord injury (SCI), but its mechanism requires elucidation.
- This study investigates HDAC3's role in neuroinflammation and microglial function following SCI.
Purpose of the Study:
- To explore the effects of HDAC3 inhibition on neuroinflammation and microglial function after spinal cord injury.
- To elucidate the underlying molecular mechanisms, specifically focusing on the SIRT1/Nrf2 signaling pathway.
Main Methods:
- Rats with SCI were treated with RGF966 (HDAC3 inhibitor) or vehicle.
- Neurological function was assessed using the Basso Beattie Bresnahan (BBB) scale and inclined plane test.
- Microglial activation, inflammatory markers, blood-spinal cord barrier integrity, and the SIRT1/Nrf2 pathway were analyzed using immunofluorescence, western blotting, and qPCR.
Main Results:
- HDAC3 inhibition improved neurological function, reduced BBB permeability and brain edema, and preserved junction protein levels.
- Inhibition of HDAC3 suppressed microglial activation and decreased pro-inflammatory factor levels.
- HDAC3 inhibition upregulated SIRT1 expression and promoted Nrf2 nuclear accumulation and activity, enhancing downstream antioxidant enzyme expression.
Conclusions:
- HDAC3 inhibition protects against spinal cord injury by mitigating microglial activation and inflammation via the SIRT1/Nrf2 pathway.
- HDAC3 represents a promising therapeutic target for treating spinal cord injury.
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