Hydrogen Gas Alleviates Sepsis-Induced Brain Injury by Improving Mitochondrial Biogenesis Through the Activation of PGC-α in Mice.

Abstract

Sepsis-associated encephalopathy (SAE) develops in roughly one-third of septic patients, yet effective countermeasures remain scarce. Using a cecal ligation and puncture mouse model, this study examined whether 2% H2 gas inhalation (1 h sessions beginning at 1 h and 6 h post-surgery) could mitigate brain injury. Outcomes included 7-day survival, Y-maze cognitive performance, hippocampal CA1 histology (Nissl and TUNEL staining), mitochondrial membrane potential, ATP levels, respiratory chain complex I and II activities, and protein expression of PGC-1α, NRF2, and Tfam. H2-treated mice showed improved survival, better cognitive scores, and enhanced mitochondrial function alongside upregulated biogenesis markers. Co-administration of the PGC-1α inhibitor SR-18292 reversed these improvements, indicating that PGC-1α-driven mitochondrial biogenesis is central to the neuroprotective action of hydrogen gas in septic mice.

Mechanism

H2 gas activates PGC-1α, which in turn upregulates NRF2 and Tfam, promoting mitochondrial biogenesis and thereby restoring mitochondrial membrane potential, ATP production, and complex I activity while reducing apoptosis in the septic brain.