[Gastrodin alleviates hypobaric hypoxia-induced brain injury in rats by reducing neuronal ferroptosis via the P53/SLC7A11/GPX4 signaling axis].

OBJECTIVES

To investigate the neuroprotective effect of gastrodin (GAS) against hypobaric hypoxia (HH)-induced brain injury in rats and the underlying mechanism.

METHODS

Twenty-four adult SD rats were randomized equally into normoxic control group, HH model group, low-dose (100 mg/kg) GAS group (HH+GAS-L group), and high-dose (200 mg/kg) GAS group (HH+GAS-H group). In the latter 3 groups, the rats were exposed to HH in a hypobaric oxygen chamber for 24 h to simulate the condition at an altitude of 6000 m, and GAS was administered intraperitoneally once daily for 7 days. Cerebral cortex tissues were collected for analysis of P53, SLC7A11, and GPX4 protein expressions using Western blotting and for determination of the levels of reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and ferrous ion (Fe²⁺). In cultured HT22 neurons exposed to oxygen-glucose deprivation (OGD), the effects of GAS (500 μmol/L), nutlin-3 (a P53 agonist; 10 μmol/L) or their combination were examined on ferroptosis-related protein expressions, intracellular ROS, lipid peroxidation, MDA, GSH, cell viability, mitochondrial membrane potential, and Fe²⁺ levels.

RESULTS

In the rat models of HH, GAS treatment significantly inhibited P53 expression, upregulated SLC7A11 and GPX4 proteins, markedly reduced Fe²⁺, ROS, and MDA levels, and increased GSH content in the cerebral cortex. In cultured HT22 neurons, GAS treatment effectively alleviated OGD-induced cell ferroptosis as shown by decreased P53 expression, increased SLC7A11 and GPX4 expressions, and lowered levels of intracellular ROS generation, lipid peroxidation, and Fe²⁺ accumulation, along with obvious restoration of GSH levels, cell viability, and mitochondrial membrane potential. The protective effects of GAS was markedly attenuated by activation of the P53 pathway using nutlin-3.

CONCLUSIONS

GAS produces neuroprotective effects against HH-induced brain injury in rats by inhibiting neuronal ferroptosis via regulating the P53/SLC7A11/GPX4 signaling pathway.