Targeting the Calcium–mtDNA–cGAS-STING Signaling Nexus: A Novel Redox Mechanism for Nimodipine’s Neuroprotection in Traumatic Brain Injury
Xiaoming Feng, Wei Cao, Xuning Shen, Huijie Yu, Guoping Shen, Qifeng Qian, Yunfeng Xu, Jun Fang, Dongjun Xu, Yan XuObjective:
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
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
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 Ca
2+
-mtDNA-cGAS-STING axis contributes to TBI pathology and that nimodipine may serve as a potential multitarget therapy.