Methane-Rich Saline Alleviates CA/CPR Brain Injury by Inhibiting Oxidative Stress, Microglial Activation-Induced Inflammatory Responses, and ER Stress-Mediated Apoptosis

Abstract

Brain injury induced by cardiac arrest/cardiopulmonary resuscitation (CA/CPR) is the leading cause of death among patients who have recovery of spontaneous circulation (ROSC). Inflammatory response, apoptosis, and oxidative stress are proven pathological mechanisms implicated in neuronal damage. Methane-rich saline (MRS) has been proven that exerts a beneficial protectiveness impact in several models of ischemia-reperfusion injury. The goal of this paper is to ascertain the role of MRS in CA/CPR-induced brain injury and its potential mechanisms. The tracheal intubation of Sprague-Dawley (SD) rats was clamped for 6 min to establish an asphyxiating cardiac arrest model. After that, chest compressions were applied; then, MRS or saline was administered immediately post-ROSC, the rats were sacrificed, and brain tissue was collected at the end of 6 hours. We observed that MRS treatment attenuated neuronal damage in the hippocampal CA1 region by inhibiting microglial activation, leading to a decrease in the overexpression of proinflammatory cytokines such as TNF-α, IL-6, and iNOS. The results also illustrated that MRS treatment diminished apoptosis in the hippocampal CA1 region , reduced the expression of apoptosis-associated proteins Bax and cleaved caspase9, and increased Bcl-2 expression, as well as inhibited the expression of endoplasmic reticulum (ER) stress pathway-related proteins GRP78, ATF4, and CHOP. Further findings showed that MRS treatment significantly attenuated hippocampal ROS and MDA levels and increased GSH and SOD antioxidant factor levels, which indicated that MRS treatment could inhibit oxidative stress. Our results suggest that MRS exerts a protective effect against CA/CPR brain injury, by inhibiting oxidative stress, microglial activation-induced inflammatory responses, and ER stress-mediated apoptosis.

Neuroinflammation and Its Impact on the Pathogenesis of COVID-19

“…The increase of these cytokines was associated with acrylamide neurotoxicity in both in vivo and in vitro experimental models ( 69 ). A recent study has shown that pharmacological inhibition of microglial activation significantly reduced neuronal death ( 70 ). Neuroinflammation-induced neuron injury can also release cytotoxic and chemotactic mediators, which subsequently can activate surrounding microglial cells and exacerbate the microglia-mediated neuroinflammation ( 71 , 72 ).…”

A Nanotherapy of Octanoic Acid Ameliorates Cardiac Arrest/Cardiopulmonary Resuscitation-Induced Brain Injury via RVG29- and Neutrophil Membrane-Mediated Injury Relay Targeting

“…These pathophysiological processes initiate a series of cellular responses including mitochondrial dysfunction, energy-metabolic disorder, harmful metabolite accumulation, reactive oxygen species (ROS) production, inflammatory cytokine upregulation, endothelial cell activation, immune cell migration, and cerebral cell necrosis and apoptosis, which ultimately result in neurological impairment. 4,7,8 Although progress has been made with the application of therapeutic hypothermia, the protective effects of this treatment remain far from ideal, due to severe adverse effects including hyperglycemia, arrhythmia, and infection. 9 Thus, investigating and developing efficacious therapeutic treatments for CA/CPR-induced brain IRI is urgently needed.…”

“…As one of the leading causes of death, cardiac arrest (CA) impacts millions of people, with only 1.0–10% of these individuals surviving to be discharged from the hospital each year. , Despite successful cardiopulmonary resuscitation (CPR) and return of spontaneous circulation (ROSC) after CA, most survivors still suffer multiple organ injuries among which brain lesions predominate, and only 5–17% of these patients can avoid serious neurological problems in the long term. − Brain injury following CA/CPR is mainly associated with ischemia–reperfusion (I/R) injury (IRI), , which is a sudden restricted supply of blood to the brain caused by CA that is followed by the restoration of blood flow and reoxygenation through ROSC. These pathophysiological processes initiate a series of cellular responses including mitochondrial dysfunction, energy-metabolic disorder, harmful metabolite accumulation, reactive oxygen species (ROS) production, inflammatory cytokine upregulation, endothelial cell activation, immune cell migration, and cerebral cell necrosis and apoptosis, which ultimately result in neurological impairment. ,, Although progress has been made with the application of therapeutic hypothermia, the protective effects of this treatment remain far from ideal, due to severe adverse effects including hyperglycemia, arrhythmia, and infection . Thus, investigating and developing efficacious therapeutic treatments for CA/CPR-induced brain IRI is urgently needed.…”

Baicalein Relieves Brain Injury via Inhibiting Ferroptosis and Endoplasmic Reticulum Stress in a Rat Model of Cardiac Arrest

“…Specifically, unfolded proteins accumulate, and glucose-regulated protein 78 (GRP78) is separated into three proteins: inositol-requiring protein-1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (ATF6). The activation of the PERK pathway promoted the translation of activating transcription factor 4 (ATF4), and intense ER stress might cause the C/EBP homologous protein (CHOP) mediated cell apoptosis, which aggravated cell damage (13). Moreover, baicalein reduced liver damage by inhibiting ER stress and the trigger of autophagy (14).…”