Hydrogen gas post‑conditioning attenuates early neuronal pyroptosis in a rat model of subarachnoid hemorrhage through the mitoK_ATP signaling pathway

Abstract

Neuronal pyroptosis serves an important role in the progress of neurologic dysfunction following subarachnoid hemorrhage (SAH), which is predominantly caused by a ruptured aneurysm. Hydrogen gas has been previously reported to be an effective anti-inflammatory agent against ischemia-associated diseases by regulating mitochondrial function. The objective of the present study was to investigate the potential neuroprotective effects of hydrogen gas post-conditioning against neuronal pyroptosis after SAH, with specific focus on the mitochondrial ATP-sensitive K + (mitoK ATP ) channels. Following SAH induction by endovascular perforation, rats were treated with inhalation of 2.9% hydrogen gas for 2 h post-perforation. Neurologic deficits, brain water content, reactive oxygen species (ROS) levels, neuronal pyroptosis, phosphorylation of ERK1/2, p38 MAPK and pyroptosis-associated proteins IL-1β and IL-18 were evaluated 24 h after perforation by a modified Garcia method, ratio of wet/dry weight, 2',7'-dichlorofluorescin diacetate, immunofluorescence and western blot assays, respectively. An inhibitor of the mitoK ATP channel, 5-hydroxydecanoate sodium (5-HD), was used to assess the potential role of the mitoK ATP -ERK1/2-p38 MAPK signal pathway. Hydrogen gas post-conditioning significantly alleviated brain edema and improved neurologic function, reduced ROS production and neuronal pyroptosis, suppressed the expression of IL-1β and IL-18 whilst upregulating ERK1/2 phosphorylation, but downregulated p38 MAPK activation 24 h post-SAH. These aforementioned effects neuroprotective were partially reversed by 5-HD treatment. Therefore, these observations suggest that post-conditioning with hydrogen gas ameliorated SAH-induced neuronal pyroptosis at least in part through the mitoK ATP /ERK1/2/p38 MAPK signaling pathway.

An Update on Antioxidative Stress Therapy Research for Early Brain Injury After Subarachnoid Hemorrhage

“…Furthermore, sodium/hydrogen exchanger 1 participates in EBI activated by SAH via mediating OS (Song et al, 2019). As abovementioned earlier, a recent study shows that postconditioning with hydrogen gas ameliorated SAHinduced neuronal pyroptosis (Zhang C. S. et al, 2021). Produced endogenously through HO, carbon oxide (CO) minimizes neurobehavioral deficits, indicating that posttreatment with CO gas or CO-donors can be further tested as a potential therapy against SAH (Kamat et al, 2019).…”

“…Admittedly, various mechanisms or contributors to early injury will consequently result in cell death of the catastrophic ictus. Nowadays, the cell death processes in study include apoptosis, necrosis, autophagy ( Dou et al, 2017 ; Sun C. et al, 2019 ; Sun C. M. et al, 2019 ), necroptosis ( Kooijman et al, 2014 ; Chen et al, 2017 , 2018 , 2019 ; Xie et al, 2017 ; Yang C. et al, 2018 ; Yuan et al, 2019 ; Fang et al, 2020 ; Xu H. et al, 2021 ), pyroptosis ( Yuan et al, 2020 ; Xu P. et al, 2021 ; Zhang C. S. et al, 2021 ), and ferroptosis ( Lee et al, 2010 ; Zhao et al, 2018 ; Fang et al, 2020 ; Sq et al, 2020 ; Cao et al, 2021 ; Li et al, 2021 ; Qu et al, 2021 ). All but the former two well-known cell death mechanisms remain novel types and cutting-edge hot topics.…”

“…Recently, SAH-induced synaptic impairments mitigated by NEC-1 in the hippocampus that inhibits necroptosis in relation to the CREB-BDNF pathway were verified ( Yang C. et al, 2018 ). Moreover, another type of cell death, SAH-induced neuronal pyroptosis, is ameliorated in part by postconditioning with hydrogen gas through the mitoK ATP /ERK1/2/p38 MAPK signaling pathway ( Zhang C. S. et al, 2021 ). Unlike other types of cell death, such as necrosis and apoptosis, ferroptosis is a regulated process caused by an imbalance of the redox system.…”

Hydrogen gas post‑conditioning alleviates cognitive dysfunction and anxiety‑like behavior in a rat model of subarachnoid hemorrhage

“…Briefly, rats were anesthetized with sevoflurane (7-8% for induction, 3-4% for maintenance), intubated and ventilated at a tidal volume of 4-5 ml/1,000 g body weight (fraction of inspired oxygen=40%) using a ventilator (ALC-V; Shanghai Alcott Biological Technology, Inc.) with continuous body temperature control at 36.0±0.5˚C using a heating pad. The oxygen concentration was set to 40% during surgical preparation and SAH, as 40% of oxygen could lead to 99-100% oxygen saturation during mechanical ventilation ( 24 ).…”

Molecular hydrogen is a potential protective agent in the management of acute lung injury

“…Molecular hydrogen can affect pyroptosis in various animal models by inhibiting oxidative stress and NLRP3mediated pyroptosis, alleviating myocardial I/R injury in rats (Nie et al 2021). Post-conditioning with hydrogen gas ameliorated subarachnoid hemorrhage-induced neuronal pyroptosis through the mitoK ATP /ERK1/2/p38 MAPK signaling pathway in rats (Zhang et al 2021). In the lung, the inflation of 3% molecular hydrogen during the cold ischemia phase alleviated lung I/R injury by inhibiting pyroptosis and improving graft function in rats (Zheng et al 2021a).…”