Hydrogen Inhalation Attenuates Oxidative Stress Related Endothelial Cells Injury After Subarachnoid Hemorrhage in Rats

Abstract

Background: Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular disease with poor clinical outcome. Nucleotide binding and oligomerization domainlike receptor family pyrin domain-containing 3 (NLRP3) inflammasome serves a key role in inflammatory response, which may lead to endothelial cell injury and blood-brain barrier (BBB) disruption. Hydrogen (H 2) is considered a neuroprotective antioxidant. This study was set out to explore whether hydrogen inhalation protects against SAH induced endothelial cell injury, BBB disruption, microthrombosis and vasospasm in rats. Methods: One hundred eighty-two male SD rats were used for the study. SAH was induced by endovascular perforation. H2 at a concentration of 3.3% was inhaled beginning at 0.5 h after SAH for duration of 30, 60 or 120 min, followed by single administration or once daily administration for 3 days. The temporal expression of NLRP3 and ASC in the brain was determined, with the effect of hydrogen inhalation evaluated. In addition, brain water content, oxidative stress markers, inflammasome, apoptotic markers, microthrombosis, and vasospasm were evaluated at 24 or 72 h after SAH. Results: The expression of NLRP3 and ASC were upregulated after SAH associated with elevated expression of MDA, 8-OHdG, 4-HNE, HO-1, TLR4/NF-κB, inflammatory and apoptotic makers. Hydrogen inhalation reduced the expression of these inflammatory and apoptotic makers in the vessels, brain edema, microthrombi formation, and vasospasm in rats with SAH relative to control. Hydrogen inhalation also improved short-term and long-term neurological recovery after SAH. Conclusion: Hydrogen inhalation can ameliorate oxidative stress related endothelial cells injury in the brain and improve neurobehavioral outcomes in rats following SAH. Mechanistically, the above beneficial effects might be related to, at least in part, the inhibition of activation of ROS/NLRP3 axis.

Hydrogen: A Novel Option in Human Disease Treatment

“…During the past decade, many basic and clinical studies have provided evidence supporting the view that H 2 treatment protects against CVD and improves cardiac function. Ohsawa et al discovered that consumption of HW for 6 months reduced the oxidative stress level and the volume of atherosclerotic lesions derived from macrophage accumulation in apolipoprotein E knockout mice (ApoE-/- mice) [ 87 ]. Iketani et al recently revealed that continuous administration of HW in low-density lipoprotein (LDL) receptor-deficient mice decreased the numbers of endothelial cells in the atheroma expressing the senescence factors p16INK4a and p21, as well as suppressing macrophage infiltration and TNF- α expression in the atheroma, suggesting that vascular aging can be suppressed by HW [ 88 ].…”

Potential Therapeutic Applications of Hydrogen in Chronic Inflammatory Diseases: Possible Inhibiting Role on Mitochondrial Stress

“…However, excessive inflammation driven by the inflammasome and IL-1β signaling pathways promotes breast cancer, fibrosarcoma, gastric cancer, and lung metastasis in a context-dependent manner [ 48 ]. Some literature has shown that H 2 can be involved in various models of inflammation based on mechanisms of mitochondrial oxidation inhibition and NLRP3 inflammasome activation ( Table 1 ) [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ].…”

“…NLRP3 plays an important role in the inflammatory response, which may lead to vascular endothelial cell damage and disruption of the blood-brain barrier (BBB). Zhuang et al examined the effects of H 2 gas inhalation in a rat model of SAH [ 21 ]. SAH upregulated the expression of NLRP3 and ASC, accompanied by an increase in inflammatory and apoptotic markers.…”

“…Moreover, H 2 gas inhalation also improved cerebral edema and vasospasm. They reported that the mechanism by which H 2 suppresses oxidative stress-related endothelial cell injuries may partly involve the suppression of the activation of the ROS/NLRP3 axis [ 21 ].…”

“…that can permeate the cell membrane, only H 2 is able to scavenge ·OH, which is always generated inside of mitochondria [ 13 , 14 ]. It has been shown by literature that H 2 in various animal models of inflammation may be based on mechanisms to inhibit mitochondrial oxidation and NLRP3 inflammasome activation [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. However, the ability for H 2 to inhibit mitochondrial oxidation and NLRP3 inflammasome activation is poorly understood.…”