Inhalation of hydrogen gas attenuates brain injury in mice with cecal ligation and puncture via inhibiting neuroinflammation, oxidative stress and neuronal apoptosis

• Published in: Brain research Vol. 1589; pp. 78 - 92
• Main Authors: Liu, Lingling, Xie, Keliang, Chen, Hongguang, Dong, Xiaoqing, Li, Yuan, Yu, Yang, Wang, Guolin, Yu, Yonghao
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 17-11-2014; Elsevier
• Subjects: Administration, Inhalation; Animals; Apoptosis - drug effects; Biological and medical sciences; Brain Injuries - etiology; Brain Injuries - metabolism; Brain Injuries - prevention & control; Cecum - surgery; Cognitive function; Conditioning (Psychology) - physiology; Cytokines - metabolism; Encephalitis - etiology; Encephalitis - metabolism; Encephalitis - prevention & control; Fear - physiology; Fundamental and applied biological sciences. Psychology; Hippocampus - drug effects; Hippocampus - pathology; Hydrogen - administration & dosage; Hydrogen - blood; Hydrogen gas; Inflammatory cytokines; Male; Mice; Mice, Inbred ICR; Neurology; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Nrf2; Oxidative stress; Oxidative Stress - drug effects; Sepsis; Sepsis - complications; Survival Rate; Vertebrates: nervous system and sense organs; Oxidative stress; Sepsis; Inflammatory cytokines; Cognitive function; Nrf2; Hydrogen gas; Nervous system diseases; Rodentia; Cytokine; Neuroinflammation; Cognition; Inflammation; Inhalation; Cerebral disorder; Infection; Vertebrata; Mammalia; Mouse; Cell death; Animal; Central nervous system disease; Apoptosis
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2014.09.030

Abstract During the development of sepsis, the complication in central nervous system (CNS), appearing early and frequently relative to other systems, can obviously increase the mortality of sepsis. Moreover, sepsis survivors also accompany long-term cognitive dysfunction, while the ultimate causes and effective therapeutic strategies of brain injury in sepsis are still not fully clear. We designed this study to investigate the effects of 2% hydrogen gas (H2 ) on brain injury in a mouse model of sepsis. Male ICR mice were underwent cecal ligation and puncture (CLP) or sham operation. 2% H2 was inhaled for 60 min beginning at both 1 and 6 h after sham or CLP operation, respectively. H2 concentration in arterial blood, venous blood and brain tissue was detected after H2 inhalation separately. The survival rate was observed and recorded within 7 days after sham or CLP operation. The histopathologic changes and neuronal apoptosis were observed in hippocampus by Nissl staining and TUNEL assay. The permeability of brain–blood barrier (BBB), brain water content, inflammatory cytokines, activities of antioxidant enzymes (SOD and CAT) and oxidative products (MDA and 8-iso-PGF2α) in serum and hippocampus were detected at 24 h after sham or CLP operation. The expressions of nucleus and total nuclear factor erythroid 2-related factor 2 (Nrf2) and cytoplasmic heme oxygenase-1(HO-1) in hippocampus were measured at 24 h after sham or CLP operation. We assessed their cognitive function via Y-maze and Fear Conditioning test on day 3, 5, 7 and 14 after operation. H2 treatment markedly improved the survival rate and cognitive dysfunction of septic mice. CLP mice showed obvious brain injury characterized by aggravated pathological damage, BBB disruption and brain edema at 24 h after CLP operation, which was markedly alleviated by 2% H2 treatment. Furthermore, we found that the beneficial effects of H2 on brain injury in septic mice were linked to the decreased levels of inflammatory cytokines and oxidative products and the increased activities of antioxidant enzymes in serum and hippocampus. In addition, 2% H2 inhalation promoted the expression and transposition of Nrf2 and the expression of HO-1 to mitigate brain injury in sepsis. Thus, the inhalation of hydrogen gas may be a promising therapeutic strategy to relieve brain injury in sepsis.