Neuroprotection in spinal cord ischemia-reperfusion injury: Diosmetin's role via TREM2-mediated microglial pyroptosis.

BACKGROUND

Spinal cord ischemia-reperfusion injury (SCII) is a debilitating neurological condition characterized by significant neuronal damage, largely driven by microglial pyroptosis-a form of programmed cell death linked to neuroinflammation. This study investigated the neuroprotective role of TREM2 in regulating microglial pyroptosis and evaluated Diosmetin as a modulator of TREM2 signaling in SCII.

METHODS

This study explored the role of TREM2 in regulating microglial pyroptosis and neuronal damage following SCII, using both in vivo and in vitro models. Motor function was evaluated through Tarlov scoring, and molecular changes were assessed using Western blot, chromatin immunoprecipitation, and histological analyses. We focused on the TREM2/PI3K/AKT/FOXO1/GSDMD signaling pathway and its involvement in microglial pyroptosis. Additionally, molecular docking and in vitro studies were used to explore Diosmetin, a natural compound, as a potential modulator of TREM2 activity.

RESULTS

SCII induced significant microglial pyroptosis, which was effectively reduced by TREM2 overexpression, leading to improved motor neuron function. Mechanistically, TREM2 activated the PI3K/AKT pathway, promoting FOXO1 phosphorylation and reducing Gasdermin D (GSDMD) expression, thereby inhibiting pyroptosis. Furthermore, Diosmetin was identified as a potent enhancer of TREM2's anti-pyroptotic effects, binding to TREM2 with high affinity and offering neuroprotection by enhancing the TREM2/PI3K/AKT/FOXO1 pathway.

CONCLUSION

Our findings highlight the critical role of TREM2 in controlling microglial pyroptosis and protecting against SCII-induced neuronal damage. Diosmetin presents a promising therapeutic candidate for SCII by modulating this pathway and reducing inflammation.