Targeting the Calcium-mtDNA-cGAS-STING Signaling Nexus: A Novel Redox Mechanism for Nimodipine's Neuroprotection in Traumatic Brain Injury.

OBJECTIVE

Traumatic brain injury (TBI) induces severe secondary injury where molecular mechanisms remain unclear. This study investigates the involvement of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway in this process and evaluates the neuroprotective effect of the L-type calcium channel blocker nimodipine, focusing on calcium homeostasis, mitochondrial function, and inflammatory signaling.

METHODS

Using primary neuronal and mouse TBI models, we assessed outcomes via fluorescent calcium imaging, JC-1 staining, Western blot, quantitative PCR (qPCR)/reverse transcription-quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and behavioral tests. Nimodipine was applied to inhibit L-type channels, specifically testing its role in reducing mitochondrial DNA (mtDNA) release, blocking cGAS-STING activation, and suppressing neuroinflammation.

RESULTS

TBI markedly activated the cGAS-STING pathway, increasing pro-inflammatory factors and apoptosis. In the cellular oxygen-glucose deprivation model, calcium overload was directly observed by Fluo-4 AM staining and was associated with subsequent mitochondrial permeability transition pore opening and mtDNA release, identifying this process as a key upstream event for cGAS-STING activation. Nimodipine inhibited intracellular calcium overload, reduced mitochondrial injury and mtDNA release, and consequently suppressed cGAS-STING pathway activation. Both in vivo and in vitro experiments showed dose-dependent decreases in pro-inflammatory factors, along with improved neurological function and attenuated brain tissue pathology.

CONCLUSION

Nimodipine attenuates secondary neuroinflammation and neuronal apoptosis after TBI by inhibiting calcium influx, decreasing mtDNA release, and suppressing cGAS-STING signaling. These results suggest that the Ca2+-mtDNA-cGAS-STING axis contributes to TBI pathology and that nimodipine may serve as a potential multitarget therapy. Antioxid. Redox Signal. 00, 000-000.