Salidroside orchestrates metabolic reprogramming by regulating the Hif-1 alpha signalling pathway in acute mountain sickness

Context Rhodiola crenulata (Hook. f. et Thoms.) H. Ohba (Crassulaceae) is used to prevent and treat acute mountain sickness. However, the mechanisms underlying its effects on the central nervous system remain unclear. Objective To investigate the effect of Rhodiola crenulata on cellular metabolism in the central nervous system. Materials and methods The viability and Hif-1 alpha levels of microglia and neurons at 5% O-2 for 1, 3, 5 and 24 h were examined. We performed the binding of salidroside (Sal), rhodiosin, tyrosol and p-hydroxybenzyl alcohol to Hif-1 alpha, Hif-1 alpha, lactate, oxidative phosphorylation and glycolysis assays. Forty male C57BL/6J mice were divided into control and Sal (25, 50 and 100 mg/kg) groups to measure the levels of Hif-1 alpha and lactate. Results Microglia sensed low oxygen levels earlier than neurons, accompanied by elevated expression of Hif-1 alpha protein. Salidroside, rhodiosin, tyrosol, and p-hydroxybenzyl alcohol decreased BV-2 (IC50=1.93 +/- 0.34 mM, 959.74 +/- 10.24 mu M, 7.47 +/- 1.03 and 8.42 +/- 1.63 mM) and PC-12 (IC50=6.89 +/- 0.57 mM, 159.28 +/- 8.89 mu M, 8.65 +/- 1.20 and 8.64 +/- 1.42 mM) viability. They (10 mu M) reduced Hif-1 alpha degradation in BV-2 (3.7-, 2.5-, 2.9- and 2.5-fold) and PC-12 cells (2.8-, 2.8-, 2.3- and 2.0-fold) under normoxia. Salidroside increased glycolytic capacity but attenuated oxidative phosphorylation. Salidroside (50 and 100 mg/kg) treatment increased the protein expression of Hif-1 alpha and the release of lactate in the brain tissue of mice. Conclusions These results suggest that Sal induces metabolic reprogramming by regulating the Hif-1 alpha signalling pathway to activate compensatory responses, which may be the core mechanism underlying the effect of Rhodiola crenulata on the central nervous system.

Automated summary

The study revealed that components of Rhodiola crenulata can induce metabolic reprogramming by regulating the Hif-1 alpha signaling pathway, activating compensatory responses. Microglia sensed low oxygen levels earlier than neurons, accompanied by elevated expression of Hif-1 alpha protein.