Insights into the Relation between Oxidative Stress and Malaria: A Mechanistic and Therapeutic Approach

The mortality rate due to malaria has increased tremendously in the last decade. Even though the causative agent of this disease is known, the preventive measures are not potent enough to control the spread of this disease. Malarial infection involves a strong interrelationship between oxidative stress and pathogenesis. This review addresses the various oxidative stress-related mechanisms associated with vector defense, host immunity, plasmodial pathogenesis, and corresponding therapeutic strategies. The mechanisms involving host and vector defense show both similarity and contradiction to the processes involving plasmodial pathogenesis under different circumstances. Therefore, corresponding ameliorative peculiarities are observed in the therapeutic mechanisms adopted by the anti-malarial drugs. The malarial parasite augments oxidative stress to weaken the host and exerts antioxidant effects against host defense mechanisms. However, the anti-malarial drugs induce oxidative insult to reduce parasitic load and exert antioxidant effects against parasite infection-induced oxidative stress in host. Thus, the anti-malarial drugs exhibit antioxidant activity in hosts and/or pro-oxidant activity in parasites.

Molecular Hydrogen: Redox Reactions and Possible Biological Interactions

Molecular hydrogen (H2), either as a gas or as hydrogen-rich water (HRW), is suggested to be a useful treatment for a range of human diseases and also to improve agricultural output. It is often posited that H2 accomplishes its biological action, in part, through its antioxidant effects, including reacting with hydroxyl radicals (OH˙) and peroxynitrite (ONOOˉ); however, this direct reaction has been questioned. The antioxidant effects of H2 are also often mediated by heme oxygenase-1 (HO-1), although the exact mechanism remains elusive. Alternatively, it has been proposed that H2 can propagate its effects through the reduction of Fe3+ in various redox-active proteins, which is the focus of this review. It is suggested that a systematic experimental analysis of proteins containing heme prosthetic groups would help elucidate the biological mechanisms of H2 and its development as a medical and restorative therapeutic. (First online: May 10, 2021)

Elucidation of the Role of Transient Receptor Potential Vanilloid-1 (TRPV1) Channels in Epileptogenesis

The transient receptor potential vanilloid-1 (TRPV1), previously known as the capsaicin receptor or vanilloid receptor 1 (VR1) is a nonselective cation channel that acts as an integrator of nociceptive information in sensory neurons and their sensory nerve endings with unmyelinated (C) or thin myelinated (Aδ) fibers. It is activated by capsaicin, resiniferatoxin, piperine, noxious heat (> 43ºC), protons, lipoxygenase products, and some endogenous cannabinoids. TRPV1 receptors are also expressed in the brain on neurons, glia cells and pericytes and might be involved in the modulation of epileptogenesis. TRPV1 modulates synaptic plasticity and neurotransmission, mediates long-term depression of glutamate release in the hippocampus and suppress excitatory transmission in dentate gyrus. TRPV1-knockout mice have altered susceptibility to hyperthermic seizures. Studies in vitro showed that capsaicin reduced epileptiform activity but increased neuronal discharge in excitable cells. Capsaicin given via systemic routes at low doses was shown to reduce seizures induced by kainic acid and pentylenetetrazole and to afford neuroprotection of hippocampus in vivo. These effects were associated with reduced oxidative stress and inflammation in brain. In contrast, high doses of capsaicin either elicited or enhanced seizures in animals. In addition, piperine, a TRPV1 agonist, demonstrated anti-epileptic activity in several animal models via a multiplicity of mechanisms. Moreover, non-psychotropic cannabinoids such as cannabidiol and cannabidivarin, the endocannabinoid anandamide, and acetaminophen demonstrated anti-epileptiform activity in vivo and in vitro via mechanisms that might involve TRPV1 receptors. By surveying recent research findings, this review article is intended to present the current research status on the involvement of TRPV1 receptors in epileptogenesis so as to stimulate further investigations into the detailed molecular mechanisms by which capsaicin as well as other chemical modalities impact epileptogenesis via modulating TRPV1 channels. (First online: Apr 12, 2021)

Pregabalin, a GABA Analogue Protects against Carbon Tetrachloride-Induced Oxidative Stress and Liver Injury in Rats

Pregabalin is a synthetic analogue of the neurotransmitter g-aminobutyric acid (GABA) and is used in the treatment of epilepsy and neuropathic pain. The aim of this study was to investigate the effect of pregabalin on toxic liver injury caused by the acute administration of carbon tetrachloride (CCl4). Rats were orally treated with CCl4 for two successive days either alone or along with intraperitoneal pregabalin at doses of 7 and 14 mg/kg. The control group received the vehicle (olive oil). Liver oxidative stress and damage were assessed by determining serum and/or liver tissue levels of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), DNA fragmentation, serum aminotransferases, paraoxonase-1 (PON-1), and hepatic histopathology. Results showed that CCl4 significantly (i) increased MDA and NO and decreased PON-1 in both serum and liver tissue, and (ii) decreased liver GSH content and induced marked hepatic DNA fragmentation. CCl4 treatment caused liver tissue injury as evidenced by significantly increased serum aminotransferases. In line with the above biochemical changes, the liver of CCl4-treated rats exhibited massive steatosis, vacuolar degeneration, cloudy swelling, and necrosis. In CCl4-treated rats, pregabalin given at the dose of 14 mg/kg significantly reduced the increments in MDA, NO, serum aminotransferases, and hepatic DNA fragmentation. Liver GSH was unaltered but hepatic and serum PON-1 activity increased after administering pregabalin which also improved, though not normalized, liver tissue histopathology. Collectively, these results suggest that the administration of pregabalin is associated with a reduction in experimental liver injury caused by CCl4. (First online: Apr 12, 2021)

Assessing Bioenergetic Function in Response to Reactive Oxygen Species in Neural Cells

In this study, we characterized the bioenergetic response of the Lund human mesencephalic (LUHMES) cell line and a mouse astrocyte cell line to oxidative stress. Extracellular hydrogen peroxide (H2O2) levels and bioenergetic response were investigated in these cell lines after exposure to paraquat (PQ), a redox cycling compound that causes oxidative stress in cells. We used extracellular flux analysis to measure mitochondrial function in adherent astrocytes and LUHMES cells. Extracellular H2O2 was measured fluorometrically. H2O2 levels increased in both cell lines after exposure to 5 µM PQ for 18 h; however, the extent of H2O2 increase with astrocytes was significantly lower than that with LUHMES cells (33% vs. 67%). Measurements of basal mitochondrial respiration showed that PQ almost completely eliminated oxygen consumption rate (OCR) in astrocytes and significantly reduced it in LUHMES cells. Notably, OCR in LUHMES cells was higher than that in astrocytes, indicating that neuronal cells maintain higher oxidative metabolism than glial cells, which is also consistent with higher energy demands of the neuronal cells. Moreover, LUHMES cells exhibited a higher amount of adenosine triphosphate (ATP) being produced by oxidative phosphorylation than by glycolysis. In contrast, astrocytes demonstrated a higher glycolytic capacity and glycolytic reserve than LUHMES cells and higher ATP production rate by glycolysis than its production by mitochondrial oxidative metabolism. Collectively, this study showed the differential bioenergetic responses between astrocytes and LUHMES cells in responding to oxidative stress and the findings may provide insights into the mitochondrial reserve capacity in neurons and astrocytes in responding to oxidative stress. (First online: Mar 30, 2021)

Mitochondrial ROS Take Central Stage in Immune Regulation

As the powerhouse of the cell for producing adenosine triphosphate (ATP), the “energy currency” for energizing aerobic life, the mitochondrion is also a major source of cellular reactive oxygen species (ROS) production. Cutting-edge research studies over the past few years have uncovered a series of previously unrecognized fundamental biological functions carried out by mitochondrial ROS. Among them is the regulation of immunity by mitochondrial ROS signaling. (First online: Mar 13, 2021) REFERENCES Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, et al. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 2005; 308(5730):1909–11. doi: https://dx.doi.org/10.1126/science.1106653. Dai DF, Santana LF, Vermulst M, Tomazela DM, Emond MJ, MacCoss MJ, et al. Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation 2009; 119(21):2789–97. doi: https://dx.doi.org/10.1161/CIRCULATIONAHA.108.822403. Lee HY, Choi CS, Birkenfeld AL, Alves TC, Jornayvaz FR, Jurczak MJ, et al. Targeted expression of catalase to mitochondria prevents age-associated reductions in mitochondrial function and insulin resistance. Cell Metab 2010; 12(6):668–74. doi: https://dx.doi.org/10.1016/j.cmet.2010.11.004. Chouchani ET, Pell VR, Gaude E, Aksentijevic D, Sundier SY, Robb EL, et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 2014; 515(7527):431–5. doi: https://dx.doi.org/10.1038/nature13909. Nickel AG, von Hardenberg A, Hohl M, Loffler JR, Kohlhaas M, Becker J, et al. Reversal of mitochondrial transhydrogenase causes oxidative stress in heart failure. Cell Metab 2015; 22(3):472–84. doi: https://dx.doi.org/10.1016/j.cmet.2015.07.008. Shadel GS, Horvath TL. Mitochondrial ROS signaling in organismal homeostasis. Cell 2015; 163(3):560–9. doi: https://dx.doi.org/10.1016/j.cell.2015.10.001. Mills EL, Kelly B, Logan A, Costa ASH, Varma M, Bryant CE, et al. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 2016; 167(2):457–70 e13. doi: https://dx.doi.org/10.1016/j.cell.2016.08.064. West AP, Brodsky IE, Rahner C, Woo DK, Erdjument-Bromage H, Tempst P, et al. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 2011; 472(7344):476–80. doi: https://dx.doi.org/10.1038/nature09973. Geng J, Sun X, Wang P, Zhang S, Wang X, Wu H, et al. Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity. Nat Immunol 2015; 16(11):1142–52. doi: https://dx.doi.org/10.1038/ni.3268. Sena LA, Li S, Jairaman A, Prakriya M, Ezponda T, Hildeman DA, et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 2013; 38(2):225–36. doi: https://dx.doi.org/10.1016/j.immuni.2012.10.020. Oberkampf M, Guillerey C, Mouries J, Rosenbaum P, Fayolle C, Bobard A, et al. Mitochondrial reactive oxygen species regulate the induction of CD8+ T cells by plasmacytoid dendritic cells. Nat Commun 2018; 9(1):2241. doi: https://dx.doi.org/10.1038/s41467-018-04686-8. Ma C, Kesarwala AH, Eggert T, Medina-Echeverz J, Kleiner DE, Jin P, et al. NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis. Nature 2016; 531(7593):253–7. doi: https://dx.doi.org/10.1038/nature16969. Scharping NE, Rivadeneira DB, Menk AV, Vignali PDA, Ford BR, Rittenhouse NL, et al. Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat Immunol 2021; 22(2):205–15. doi: https://dx.doi.org/10.1038/s41590-020-00834-9.

Clinical Research on Antioxidant-Based Modalities in 2020

This Education & Resources web page lists major clinical studies on antioxidant-based modalities or related entities in disease intervention and health promotion, which were published in highly influential journals during 2020. It should be noted that this is not intended to be a complete list, but is rather to focus on rigorously designed and well conducted high-profile randomized controlled trials (RCTs) whose findings were reported in medical or bioscience journals of the highest impact. For more comprehensive information on antioxidant-based clinical trials, the reader may refer to the ClinicalTrials.gov (https://clinicaltrials.gov), the largest clinical trials database, run by the US National Library of Medicine, that holds registrations from over 368,000 trials from 219 countries. 2020 LIST IN REVERSE CHRONOLOGICAL ORDER Feofanova et al. A Genome-wide association study discovers 46 loci of the human metabolome in the Hispanic Community Health Study/Study of Latinos. Am J Hum Genet 2020 Nov 5; 107(5):849-863. doi: https://dx.doi.org/10.1016/j.ajhg.2020.09.003. Key finding: High levels of vitamin E metabolites were associated with lower odds of coronary heart disease. Note: Vitamin E and derivatives are antioxidants, but also possess other biological activities, such as inhibition of protein kinase C-mediated signaling. Horsfall et al. Genetically raised serum bilirubin levels and lung cancer: a cohort study and Mendelian randomisation using UK Biobank. Thorax 2020 Nov; 75(11):955-964. doi: https://dx.doi.org/10.1136/thoraxjnl-2020-214756. Key finding: High serum bilirubin was associated with decreased lung cancer incidence. Note: Bilirubin is a potent antioxidant. According to Dr Davey Smith, Mendelian randomization is a method of using measured variation in genes of known function to examine the causal effect of a modifiable exposure on disease in observational studies (from the US CDC website: https://cdc.gov). A positive finding in a Mendelian randomization study provides strong evidence for a causal relationship. Morris et al. Impact of arginine therapy on mitochondrial function in children with sickle cell disease during vaso-occlusive pain. Blood 2020 Sep 17;136(12):1402-1406. doi: https://dx.doi.org/10.1182/blood.2019003672. Key finding: Arginine therapy increased mitochondrial activity and reduced oxidative stress in children with sickle cell disease with vaso-occlusive pain episodes. Note: Arginine is the substrate for nitric oxide synthetase and possesses antioxidative activities. Nitric oxide acts also as an antioxidant in biological systems. Yubero-Serrano et al. Mediterranean diet and endothelial function in patients with coronary heart disease: an analysis of the CORDIOPREV randomized controlled trial. PLoS Med 2020 Sep 9; 17(9):e1003282. doi: https://dx.doi.org/10.1371/journal.pmed.1003282. Key finding: Mediterranean diet intake led to improved endothelial function and lower ROS production. Note: Mediterranean diet is rich in antioxidants and anti-inflammatory compounds and possesses many health benefits, especially cardiovascular protection. However, the exact contribution of the antioxidant components to the health benefits of Mediterranean diet remains to be established. Cienfuegos et al. Effects of 4- and 6-h time-restricted feeding on weight and cardiometabolic health: a randomized controlled trial in adults with obesity. Cell Metab 2020 Sep 1; 32(3):366-378.e3. doi: https://dx.doi.org/10.1016/j.cmet.2020.06.018. Key finding: Time-restricted feeding reduced body weight, insulin resistance, and oxidative stress. Nathan et al. A randomized, double-blind, placebo-controlled study of pulsed, inhaled nitric oxide in subjects at risk of pulmonary hypertension associated with pulmonary fibrosis. Chest 2020 Aug; 158(2):637-645. doi: https://dx.doi.org/10.1016/j.chest.2020.02.016. Key finding: Inhaled nitric oxide led to clinical improvement in the patients with pulmonary fibrosis. Note: Nitric oxide at physiological levels acts an antioxidative and cytoprotective molecule. McEvoy et al. Vitamin C to pregnant smokers persistently improves infant airway function to 12 months of age: a randomised trial. Eur Respir J 2020 Jul 2; 1902208. doi: https://dx.doi.org/10.1183/13993003.02208-2019. Key finding: Vitamin C supplementation (0.5 g per day) to pregnant smokers improved infant airway function. Note: Vitamin C is a multitasking compound; it is an antioxidant, but also possesses many other biological functions. Chang et al. Combined treatment with hydrocortisone, vitamin c, and thiamine for sepsis and septic shock: a randomized controlled trial. Chest 2020 Jul; 158(1):174-182. doi: https://dx.doi.org/10.1016/j.chest.2020.02.065. Key finding: Null Note: Vitamin C is a multitasking compound; it is an antioxidant, but also possesses many other biological functions. Iglesias et al. Outcomes of metabolic resuscitation using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis: the ORANGES trial. Chest 2020 Jul; 158(1):164-173. doi: https://dx.doi.org/10.1016/j.chest.2020.02.049. Key finding: Combination of intravenous ascorbic acid, thiamine, and hydrocortisone significantly reduced the time to resolution of septic shock. Note: Vitamin C is a multitasking compound; it is an antioxidant, but also possesses many other biological functions. Streese et al. High-intensity interval training modulates retinal microvascular phenotype and DNA methylation of p66Shc gene: a randomized controlled trial (EXAMIN AGE). Eur Heart J 2020 Apr 14; 41(15):1514-1519. doi: https://dx.doi.org/10.1093/eurheartj/ehz196. Key finding: High-intensity interval training improved microvascular dysfunction in patients at risk, likely related to reduced p66Shc, a redox enzyme implicated in mitochondrial ROS production. Ambrosone et al. Dietary supplement use during chemotherapy and survival outcomes of patients with breast cancer enrolled in a cooperative group clinical trial (SWOG S0221). J Clin Oncol 2020 Mar 10; 38(8):804-814. doi: https://dx.doi.org/10.1200/JCO.19.01203. Key finding: Antioxidant supplement (vitamins A, C, and E; carotenoids; coenzyme Q10) both before and during breast cancer chemotherapy was associated with an adverse outcome. Note: Antioxidants have been shown to promote tumorigenesis and cancer metastasis in various experimental models in studies published in the most influential journals, including Nature and Cell. Vallerga et al. Analysis of DNA methylation associates the cystine-glutamate antiporter SLC7A11 with risk of Parkinson's disease. Nat Commun 2020 Mar 6;11(1):1238. doi: https://dx.doi.org/10.1038/s41467-020-15065-7. Key finding: Down-regulation of the SLC7A11 gene was associated with Parkinson’s disease. Note: SLC7A11 codes for a cysteine-glutamate antiporter that regulates regulating cellular levels of the reduced form of glutathione (GSH). Choi et al. Causal associations between serum bilirubin levels and decreased stroke risk: a two-sample Mendelian randomization study. Arterioscler Thromb Vasc Biol 2020 Feb; 40(2):437-445. doi: https://dx.doi.org/10.1161/ATVBAHA.119.313055. Key finding: The study supported a causal relationship between high serum levels of bilirubin and decreased stroke risk in Korean population. Note: Bilirubin is a potent antioxidant. Mendelian randomization study provides evidence for a causal relationship.

Clinical Research on Antioxidant-Based Modalities in 2021

Being updated biweekly till the end of the year, this Education & Resources web page lists major clinical studies on antioxidant-based modalities or related entities in disease intervention and health promotion, which have been published in highly influential journals during 2021. It should be noted that this is not intended to be a complete list, but is rather to focus on rigorously designed and well conducted high-profile randomized controlled trials (RCTs) whose findings were reported in medical or bioscience journals of the highest impact. For more comprehensive information on antioxidant-based clinical trials, the reader may refer to the ClinicalTrials.gov (https://clinicaltrials.gov), the largest clinical trials database, run by the US National Library of Medicine, that holds registrations from over 368,000 trials from 219 countries. 2021 LIST IN REVERSE CHRONOLOGICAL ORDER Xu et al. Edaravone dexborneol versus edaravone alone for the treatment of acute ischemic stroke: a phase III, randomized, double-blind, comparative trial. Stroke 2021 Mar; 52(3):772-780. doi: https://dx.doi.org/10.1161/STROKEAHA.120.031197. Key finding: Edaravone dexborneol (a combination of edaravone and borneol) was superior to edaravone alone in improving the clinical outcomes of the acute ischemic stroke patients. Note: Edaravone, a synthetic free radical scavenger, was approved by the US FDA in 2017 for treating amyotrophic lateral sclerosis (ALS). Borneol is a phytochemical with diverse biological activities including antioxidative and anti-inflammatory effects. Kim et al. Reactive oxygen species scavenger in acute intracerebral hemorrhage patients: a multicenter, randomized controlled trial. Stroke 2021 Feb 25; doi: https://doi.org/10.1161/STROKEAHA.120.032266. Key finding: Giving N-acetylcysteine 2000 mg/day and selenium 1600 µg/day, intravenously, for 14 days significantly improved the clinical outcomes in the acute intracerebral hemorrhage patients. Note: N-Acetylcysteine is a precursor of glutathione (GSH). Selenium acts as an antioxidant element due, at least partly, to its essentialness for the function of various selenoproteins, including selenium-dependent glutathione peroxidases (GPx). Kalstad et al. Effects of n-3 fatty acid supplements in elderly patients after myocardial infarction: a randomized, controlled trial. Circulation 2021 Feb 9; 143(6):528-539. doi: https://dx.doi.org/10.1161/CIRCULATIONAHA.120.052209. Key finding: Null Note: n-3 Fatty acids, also known as omega-3 fatty acids, possess potent antioxidative and anti-inflammatory activities. Lynch et al. Safety and efficacy of omaveloxolone in Friedreich ataxia (MOXIe Study). Ann Neurol 2021 Feb; 89(2):212-225. doi: https://dx.doi.org/10.1002/ana.25934. Key finding: Omaveloxolone significantly improved neurological function compared to placebo and is well tolerated. Note: Omaveloxolone, a synthetic oleanane triterpenoid, is an activator of Nrf2, the chief regulator of cellular antioxidant and other cytoprotective genes. Meir et al. Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial. Gut 2021 Jan 18; gutjnl-2020-323106. doi: https://dx.doi.org/10.1136/gutjnl-2020-323106. Key finding: Green-Mediterranean diet enriched with green plants and polyphenols improved non-alcoholic fatty liver disease (NAFLD). Note: Mediterranean diet and green plants (green tea) and nuts are rich in antioxidants and anti-inflammatory compounds and possess many health benefits, especially cardiovascular protection. However, the exact contribution of antioxidant components to the health benefits of Mediterranean diet remains to be established. Rinott et al. Effects of diet-modulated autologous fecal microbiota transplantation on weight regain. Gastroenterology 2021 Jan; 160(1):158-173.e10. doi: https://dx.doi.org/10.1053/j.gastro.2020.08.041. Key finding: Polyphenol-enriched diet-modulated autologous fecal microbiota transplantation attenuated weight regain and preserved glycemic control. Note: Dietary polyphenols possess antioxidative, anti-inflammatory, and many other biological activities. Zheng et al. Plasma vitamin C and type 2 diabetes: genome-wide association study and Mendelian randomization analysis in European populations. Diabetes Care 2021 Jan; 44(1):98-106. doi: https://dx.doi.org/10.2337/dc20-1328. Key finding: Null; no evidence to support an efficacy of vitamin C supplement in type 2 diabetes prevention. Note: Vitamin C is a multitasking compound; it is an antioxidant, but also possesses many other biological functions. According to Dr Davey Smith, Mendelian randomization is a method of using measured variation in genes of known function to examine the causal effect of a modifiable exposure on disease in observational studies (from the US CDC website: https://cdc.gov). A positive finding in a Mendelian randomization study provides strong evidence for a causal relationship. Luo et al. Diet-derived circulating antioxidants and risk of coronary heart disease: a Mendelian randomization study. J Am Coll Cardiol 2021 Jan 5; 77(1):45-54. doi: https://dx.doi.org/10.1016/j.jacc.2020.10.048. Key finding: Null Note: According to Dr Davey Smith, Mendelian randomization is a method of using measured variation in genes of known function to examine the causal effect of a modifiable exposure on disease in observational studies (from the US CDC website: https://cdc.gov). A positive finding in a Mendelian randomization study provides strong evidence for a causal relationship.

A List of Highly Influential Journals

This Education & Resources web page provides a list, in alphabetical order, of highly influential journals (typically with an impact factor of 10 or above) where high profile research articles on ROS may be found. This, however, is not intended to be a complete list. LIST IN ALPHABETICAL ORDER American Journal of Gastroenterology American Journal of Human Genetics American Journal of Respiratory and Critical Care Medicine Annals of Internal Medicine Annals of Neurology Autophagy Blood Brain British Medical Journal Cancer Research Cell (and Molecular Cell, Cancer Cell, Cell Metabolism, Cell Stem Cell, Developmental Cell, Cell Host Microbe) Cell Research Chest Circulation Circulation Research Current Biology EMBO J (and EMBO Molecular Medicine) European Heart Journal European Journal of Heart Failure European Respiratory Journal Gastroenterology Genes and Development Genome Biology Genome Research Gut Hepatology Immunity JAMA (and JAMA Internal Medicine, JAMA Cardiology) Journal of Allergy and Clinical Immunology Journal of the American College of Cardiology (and JACC Cardiovascular Imaging, JACC Cardiovascular Interventions, JACC Heart Failure) Journal of Cell Biology Journal of Clinical Investigation Journal of Experimental Medicine Journal of the American Chemical Society Journal of the National Cancer Institute Lancet (and Lancet Oncology, Lancet Neurology, Lancet Diabetes & Endocrinology) Microbiome Molecular Biology and Evolution Molecular Cancer Molecular Plant Nature (and Nature Genetics, Nature Medicine, Nature Methods, Nature Biotechnology, Nature Materials, Nature Nanotechnology, Nature Communications, Nature Structural & Molecular Biology, Nature Neuroscience, Nature Immunology, Nature Cell Biology, Nature Chemical Biology, Nature Microbiology, Nature Plants, Nature Chemical Biology) Neuron New England Journal of Medicine Nucleic Acids Research Plant Cell PLOS Medicine Proceedings of the National Academy of Sciences of the United States of America Science (and Science Signaling, Science Translational Medicine, Science Immunology)

Effect of Propofol and Fentanyl on Brain Oxidative Stress after Systemic Lipopolysaccharide Injection in Rats

Systemic inflammation causes brain oxidative stress, a prerequisite for neurodegeneration. In this study, we investigated the effect of the anesthetic agents propofol and fentanyl on brain oxidative stress during mild systemic endotoxemia induced by lipopolysaccharide (LPS) endotoxin. For this purpose, rats were administered LPS (400 μg/kg, intraperitoneally; i.p.), treated at the same time with different doses of propofol or fentanyl, i.p., and euthanized 4 h later. Other groups were treated with the saline, only propofol, or only fentanyl. Oxidative stress markers including malondialdehyde (MDA), nitric oxide (NO), and reduced glutathione (GSH) were determined. In addition, nuclear factor kappaB (NF-kB), paraoxonase-1 (PON-1), and butyrylcholinesterase (BChE) activities were measured in the brain tissue. Results showed that compared with the saline group, administration of LPS caused a marked and significant increase in brain MDA and NO combined with depletion of GSH and decreased PON-1 and BChE activities. Additionally, the active form of NF-kB was significantly increased in the brain of LPS only-treated rats. Treatment with propofol or fentanyl led to a marked and significant decrease in the levels of brain MDA and NO together with a significant increase in GSH and restoration of PON-1 and BChE activities. Furthermore, lower levels of active form of NF-kB were found following treatment with propofol or fentanyl compared with those in the LPS only group. Collectively, these results suggest that propofol and fentanyl exhibit an antioxidant action and attenuate the endotoxin-induced brain oxidative stress.