Hydrogen Gas Attenuates Hypoxic-Ischemic Brain Injury via Regulation of the MAPK/HO-1/PGC-1a Pathway in Neonatal Rats

Abstract

Neonatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of death in neonates with no effective treatments. Recent advancements in hydrogen (H2) gas offer a promising therapeutic approach for ischemia reperfusion injury; however, the impact of this approach for HIE remains a subject of debate. We assessed the therapeutic effects of H2 gas on HIE and the underlying molecular mechanisms in a rat model of neonatal hypoxic-ischemic brain injury (HIBI). H2 inhalation significantly attenuated neuronal injury and effectively improved early neurological outcomes in neonatal HIBI rats as well as learning and memory in adults. This protective effect was associated with initiation time and duration of sustained H2 inhalation. Furthermore, H2 inhalation reduced the expression of Bcl-2-associated X protein (BAX) and caspase-3 while promoting the expression of Bcl-2, nuclear factor erythroid-2-related factor 2, and heme oxygenase-1 (HO-1). H2 activated extracellular signal-regulated kinase and c-Jun N-terminal protein kinase and dephosphorylated p38 mitogen-activated protein kinase (MAPK) in oxygen-glucose deprivation/reperfusion (OGD/R) nerve growth factor-differentiated PC12 cells. Inhibitors of MAPKs blocked H2-induced HO-1 expression. HO-1 small interfering RNA decreased the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and sirtuin 1 (SIRT1) and reversed the protectivity of H2 against OGD/R-induced cell death. These findings suggest that H2 augments cellular antioxidant defense capacity through activation of MAPK signaling pathways, leading to HO-1 expression and subsequent upregulation of PGC-1α and SIRT-1 expression. Thus, upregulation protects NGF-differentiated PC12 cells from OGD/R-induced oxidative cytotoxicity. In conclusion, H2 inhalation exerted protective effects on neonatal rats with HIBI. Early initiation and prolonged H2 inhalation had better protective effects on HIBI. These effects of H2 may be related to antioxidant, antiapoptotic, and anti-inflammatory responses. HO-1 plays an important role in H2-mediated protection through the MAPK/HO-1/PGC-1α pathway. Our results support further assessment of H2 as a potential therapeutic for neurological conditions in which oxidative stress and apoptosis are implicated.

Molecular and Cellular Mechanisms Associated with Effects of Molecular Hydrogen in Cardiovascular and Central Nervous Systems

“…The fact that the effects of hydrogen on signaling pathways are not always unidirectional is further confirmed in the study of Wang et al [ 61 ], where hydrogen exerted neuroprotection in a cellular in vitro model of traumatic brain injury through activation of the miR-21/PI3K/Akt/GSK-3β signaling pathway. Activation of the PI3K/Akt kinase pathway has also been found to be related to the neuroprotective effects of molecular hydrogen against neurologic damage and apoptosis in early brain injury induced by subarachnoid hemorrhage [ 106 ].…”

“…Molecular hydrogen reduces oxidative stress not only directly, but also indirectly by inducing antioxidation systems, including heme oxygenase-1 (HO-1) [ 60 , 61 ], superoxide dismutase (SOD) [ 7 , 9 ], catalase [ 62 ], and myeloperoxidase ( Figure 1 ) [ 62 , 63 ]. In a rat model of traumatic brain injury, it was observed that the beneficial effects of hydrogen inhalation were mediated by the reduction of oxidative stress and the stimulation of enzymatic activities of the endogenous antioxidants SOD and catalase [ 64 ].…”

Niche Cells Crosstalk In Neuroinflammation After Traumatic Brain Injury

“…Apart from the regulation of the inflammation, methods are exploited to improve the oxygenation or metabolism status, and weaken neuronal pyroptosis 128 . Hyperbaric oxygen therapy and Hydrogen gas both seem to be effective to attenuate the injury extent 129 . Lactate metabolism in brain is an essential feature after TBI 130 , and hypertonic sodium lactate solution is proved to reverse brain oxygenation and metabolism dysfunction after traumatic brain injury through vasodilatory, mitochondrial, and anti-edema effects 131 .…”

Current Therapies for Neonatal Hypoxic–Ischaemic and Infection-Sensitised Hypoxic–Ischaemic Brain Damage

“…Furthermore, H 2 treatment improves behaviour and cognitive function assessed through Morris water maze test for spatial learning and locomotor activity. Additionally, in a P7 rat HI model, H 2 significantly attenuates neuronal injury and improves early neurological outcomes by reducing Bax and caspase-3 expression ( Wang et al, 2020 ). In a piglet model of HI, H 2 combined with TH, improved walking ability and decreased TUNEL positive cell death in dorsal cortex ( Htun et al, 2019 ).…”