Study of the correlation between the anti–ischemic stroke mechanism of 4-hydroxybenzaldehyde and its response to reactive oxygen species in brain metabolism

The active ingredient of Gastrodia elata, 4-hydroxybenzaldehyde (4-HBd), can rapidly enter the brain and undergo massive oxidation to produce the metabolite 4-hydroxybenzoic acid, which has no significant activity after equal dose gavage. It is crucial to clarify the metabolic pathway of 4-HBd and its correlation with the anti-ischemic stroke mechanism. The objective of this study was to explore the possible mechanism of 4-HBd in clearing reactive oxygen species (ROS) and protecting blood-brain barrier from oxidative stress damage during brain metabolism from the perspective of ROS response. A rat model of cerebral ischemia-reperfusion injury and a cellular oxidative stress response model were replicated to simulate the accumulation process of ROS in the brain. The changes in ROS and peroxidation products before and after 4-HBd intervention were detected, and the changes in oxidative metabolism were also measured to confirm the correlation between antioxidant stress damage and ROS capture/clearance in oxidative metabolism. 4-HBd has significant antioxidant stress resistance both in vitro and in vivo, and can reduce the levels of malondialdehyde and 4-hydroxy-2-nonenal in ischemic brain tissue. It can capture O2⋅- and ⋅OH in vitro and use the captured ROS to oxidize and metabolize 4-hydroxybenzoic acid. The oxidative metabolism process of 4-HBd in the brain is one of its mechanisms for exerting antioxidant stress damage and protecting blood-brain barrier. SIGNIFICANCE STATEMENT: The active ingredient 4-hydroxybenzaldehyde of Gastrodia elata can be converted into metabolite 4-hydroxybenzoic acid in the brain mainly through oxidative metabolic pathway. The mechanism of its action against oxidative stress damage of blood-brain barrier is related to the oxidative metabolic process in the brain that traps/clears reactive oxygen species and forms stable intermediates to terminate the free radical chain reaction. This is one of the main mechanisms of 4-hydroxybenzaldehyde's anti-ischemic stroke effect in the brain.