Gastrodin Attenuates Cerebral Ischemia–Reperfusion Injury by Enhancing Mitochondrial Fusion and Activating the AMPK-OPA1 Signaling Pathway

Background

Cerebral ischemia–reperfusion (I/R) injury is a critical pathological process in stroke, characterized by disrupted energy metabolism, inflammatory responses, and mitochondrial dysfunction. Targeting mitochondrial dynamics presents promising strategies for alleviating brain injury. This study investigates the role and mechanism of Gastrodin (Gas) in regulating mitochondrial dynamics and mitigating cerebral I/R injury via activation of the AMPK-OPA1 signaling pathway.

Methods

An in vitro oxygen–glucose deprivation/reperfusion (OGD/R) model and an in vivo middle cerebral artery occlusion/reperfusion (MCAO/R) model were used to assess the effects of Gas on inflammation, mitochondrial function, and energy metabolism. Immunofluorescence, western blotting (WB), reverse-transcription PCR (RT-PCR), JC-1 staining, and molecular docking techniques were employed for analysis.

Results

Gas activated the AMPK-OPA1 signaling pathway, promoting mitochondrial fusion, restoring membrane potential, enhancing ATP production, and rebalancing NAD⁺/NADH levels. Additionally, Gas significantly suppressed I/R-induced inflammatory responses, reduced neuronal damage, and decreased infarct volume. Notably, its protective effects on mitochondrial fusion and neuroprotection were abolished under AMPK silencing, highlighting the critical role of the AMPK-OPA1 pathway.

Conclusion

Gas alleviates cerebral I/R injury by regulating mitochondrial dynamics via the AMPK-OPA1 signaling pathway. These findings provide a theoretical basis for the therapeutic application of Gas in stroke and offer new insights into mitochondrial-targeted treatment strategies.