Curcumin as a Potential Therapeutic Agent for Mitigating Carbon Monoxide Poisoning: Evidence from an Experimental Rat Study.

BACKGROUND Carbon monoxide (CO) is a poisonous gas and causes tissue damage through oxidative stress. We aimed to investigate the protective value of curcumin in CO poisoning. MATERIAL AND METHODS Twenty-four female Spraque Dawley rats were divided into 4 subgroups: controls (n=6), curcumin group (n=6), CO group (n=6), and curcumin+CO group (n=6). The experimental group was exposed to 3 L/min of CO gas at 3000 ppm. Curcumin was administered intraperitoneally at a dosage of 50 mg/kg. Hippocampal tissues were removed and separated for biochemical and immunohistochemical analysis. Tissue malondialdehyde (MDA) levels, nitric oxide (NO) levels, and superoxide dismutase (SOD) and catalase (CAT) activities were assayed spectrophotometrically, and serum asymmetric dimethylarginine (ADMA) were measured using the ELISA technique. Tissue Bcl-2 levels were detected by the immunohistochemistry method. RESULTS Tissue CAT and SOD activities and NO levels were significantly lower, and MDA and serum ADMA levels were higher in the CO group than in the control group (P<0.001). The curcumin+CO group had higher CAT activities (P=0.007) and lower MDA than the CO group (P<0.001) and higher ADMA levels than the control group (P=0.023). However, there was no significant difference observed for tissue SOD activity or NO levels between these 2 groups. In the curcumin+CO group, the Bcl-2 level was higher than that in the CO group (P=0.017). CONCLUSIONS The positive effect of curcumin on CAT activities, together with suppression of MDA levels, has shown that curcumin may have a protective effect against CO poisoning.

Hyperbaric oxygenation improve red blood cell deformability in patients with acute or chronic inflammation.

INTRODUCTION: Red blood cells (RBC) are one of the key elements of the microcirculation. Their ability to pass through capillaries and to deliver oxygen to cells is due to their large degree of deformability linked to the characteristics of the RBC membrane. Alterations in RBC deformability as a result of membrane damage, linked in part to increased synthesis of reactive oxygen species (ROS), can be observed in several diseases, such as sepsis, and may contribute to the altered microcirculation observed in these pathologies. Hyperbaric oxygen therapy (HBOT), with inhalation of 100 % oxygen, has been proposed in several acute or chronic pathologies, including carbon monoxide poisoning. OBJECTIVE: We investigated the effects of HBOT on oxidative stress from ROS produced by myeloperoxidase (MPO) and on RBC deformability in patients with acute or chronic inflammation (n = 10), in patients with acute carbon monoxide poisoning (n = 10), and in healthy volunteers (n = 10). METHODS: RBC deformability was evaluated before and after HBOT in the various populations using the ektacytometry technique (Laser-assisted Optical Rotational Red Cell Analyzer - LORRCA). Deformability was determined by the elongation index (EI) in relation to the shear stress (SS) over a range of 0.3 to 50 Pa. Oxidative stress was estimated through changes in proteins (chlorotyrosine and homocitrulline) induced by MPO activity measured by liquid chromatography-tandem mass spectrometry analysis. RESULTS: Before HBOT, EI was significantly lower in patients with acute or chronic inflammation than in healthy volunteers and patients with acute carbon monoxide poisoning for the majority of SS values studied. After one session of HBOT, the EI was significantly higher than before HBOT for SS values of 1.93 Pa or higher in patients with acute or chronic inflammation. This effect remains constant after 10 sessions. There were no differences before and after HBOT in protein or amino acid oxidation due to ROS generation mediated by MPO in the three populations. CONCLUSIONS: Our results confirm altered RBC deformability in patients with acute and chronic conditions associated with an underlying inflammatory process. HBOT improves deformability only after one session and therefore may improve microcirculation in this population. According to our results, this improvement does not seem mediated by the ROS pathway via MPO. These results need to be confirmed in a larger population.

Metabolic changes during carbon monoxide poisoning: An experimental study.

Carbon monoxide (CO) is the leading cause of death by poisoning worldwide. The aim was to explore the effects of mild and severe poisoning on blood gas parameters and metabolites. Eleven pigs were exposed to CO intoxication and had blood collected before and during poisoning. Mild CO poisoning (carboxyhaemoglobin, COHb 35.2 ± 7.9%) was achieved at 32 ± 13 minutes, and severe poisoning (69.3 ± 10.2% COHb) at 64 ± 23 minutes from baseline (2.9 ± 0.5% COHb). Blood gas parameters and metabolites were measured on a blood gas analyser and nuclear magnetic resonance spectrometer, respectively. Unsupervised principal component, analysis of variance and Pearson's correlation tests were applied. A P-value ≤ .05 was considered statistically significant. Mild poisoning resulted in a 28.4% drop in oxyhaemoglobin (OHb) and 12-fold increase in COHb, while severe poisoning in a 65% drop in OHb and 24-fold increase in COHb. Among others, metabolites implicated in regulation of metabolic acidosis (lactate, P < .0001), energy balance (pyruvate, P < .0001; 3-hydroxybutyrc acid, P = .01), respiration (citrate, P = .007; succinate, P = .0003; fumarate, P < .0001), lipid metabolism (glycerol, P = .002; choline, P = .0002) and antioxidant-oxidant balance (glutathione, P = .03; hypoxanthine, P < .0001) were altered, especially during severe poisoning. Our study adds new insights into the deranged metabolism of CO poisoning and leads the way for further investigation.

A neuroglobin-based high-affinity ligand trap reverses carbon monoxide-induced mitochondrial poisoning.

Carbon monoxide (CO) remains the most common cause of human poisoning. The consequences of CO poisoning include cardiac dysfunction, brain injury, and death. CO causes toxicity by binding to hemoglobin and by inhibiting mitochondrial cytochrome c oxidase (CcO), thereby decreasing oxygen delivery and inhibiting oxidative phosphorylation. We have recently developed a CO antidote based on human neuroglobin (Ngb-H64Q-CCC). This molecule enhances clearance of CO from red blood cells in vitro and in vivo Herein, we tested whether Ngb-H64Q-CCC can also scavenge CO from CcO and attenuate CO-induced inhibition of mitochondrial respiration. Heart tissue from mice exposed to 3% CO exhibited a 42 ± 19% reduction in tissue respiration rate and a 33 ± 38% reduction in CcO activity compared with unexposed mice. Intravenous infusion of Ngb-H64Q-CCC restored respiration rates to that of control mice correlating with higher electron transport chain CcO activity in Ngb-H64Q-CCC-treated compared with PBS-treated, CO-poisoned mice. Further, using a Clark-type oxygen electrode, we measured isolated rat liver mitochondrial respiration in the presence and absence of saturating solutions of CO (160 µm) and nitric oxide (100 µm). Both CO and NO inhibited respiration, and treatment with Ngb-H64Q-CCC (100 and 50 µm, respectively) significantly reversed this inhibition. These results suggest that Ngb-H64Q-CCC mitigates CO toxicity by scavenging CO from carboxyhemoglobin, improving systemic oxygen delivery and reversing the inhibitory effects of CO on mitochondria. We conclude that Ngb-H64Q-CCC or other CO scavengers demonstrate potential as antidotes that reverse the clinical and molecular effects of CO poisoning.

Mitochondrial toxins potentiate hydroxyl radical production in rat striatum during carbon monoxide poisoning.

Hydroxyl radical (•OH) production in the rat striatum during carbon monoxide (CO) poisoning, which inhibits complex IV, was enhanced synergistically by malonate, a mitochondrial complex II inhibitor, but not N-methyl-4-phenylpyridinium or NaCN, complex I and IV inhibitors, respectively. No such enhancement appeared in the case of NaCN combined with malonate. Intrastriatal dopamine, which is involved in •OH production by malonate, did not synergistically enhance CO-induced •OH production. Diphenyleneiodonium, a nonselective NADPH oxidase inhibitor, partly suppressed the potentiation of CO-induced •OH production by malonate. Impairment of mitochondrial functions might potentiate oxidative stress and intensify CO toxicity in the brain.

Ex vivo use of cell-permeable succinate prodrug attenuates mitochondrial dysfunction in blood cells obtained from carbon monoxide-poisoned individuals.

The purpose of this study was to evaluate a new pharmacological strategy using a first-generation succinate prodrug, NV118, in peripheral blood mononuclear cells (PBMCs) obtained from subjects with carbon monoxide (CO) poisoning and healthy controls. We obtained human blood cells from subjects with CO poisoning and healthy control subjects. Intact PBMCs from subjects in the CO and Control group were analyzed with high-resolution respirometry measured in pmol O2 per second per 10-6 PBMCs. In addition to obtaining baseline respiration, NV118 (100 µM) was injected, and the same parameters of respiration were obtained for comparison in PBMCs. We measured mitochondrial dynamics with microscopy with the same conditions. We enrolled 37 patients (17 in the CO group and 20 in the Control group for comparison) in the study. PMBCs obtained from subjects in the CO group had overall significantly lower respiration compared with the Control group (P < 0.0001). There was a significant increase in respiration with NV118, specifically with an increase in maximum respiration and respiration from complex II and complex IV (P < 0.0001). The mitochondria in PBMCs demonstrated an overall increase in net movement compared with the Control group. Our results of this study suggest that the therapeutic compound, NV118, increases respiration at complex II and IV as well as restoration of mitochondrial movement in PBMCs obtained from subjects with CO poisoning. Mitochondrial-directed therapy offers a potential future strategy with further exploration in vivo.

Carbon monoxide increases utero-placental angiogenesis without impacting pregnancy specific adaptations in mice.

BACKGROUND: Cigarette smokers have a reduced risk of developing preeclampsia, possibly attributed to an increase in carbon monoxide (CO) levels. Carbon monoxide is a gasotransmitter that has been implicated in maintaining vascular tone, increasing angiogenesis, and reducing inflammation and apoptosis at physiological concentrations. Moderately increasing CO concentrations may have therapeutic potential to prevent or treat preeclampsia; however, the effects of CO on pregnancy are under studied. Our objective was to investigate the effect of CO on major angiogenic and inflammatory markers in pregnancy, and to evaluate the effect of CO on indicators of placental health. FINDINGS: Pregnant CD-1 mice were constantly exposed to either ambient air or 250 ppm CO from conception until gestation day (GD)10.5 or GD16.5. Using a qRT-PCR array, we identified that CO increased expression of major angiogenic genes at the implantation site on GD10.5, but not GD16.5. Pro-inflammatory cytokines in the plasma and tissue lysates from implantation sites in treated mice were not significantly different compared to controls. Additionally, CO did not alter the implantation site phenotype, in terms of proliferative capacity, invasiveness of trophoblasts, or abundance of uterine natural killer cells. CONCLUSIONS: This study suggests that CO exposure is pro-angiogenic at the maternal-fetal interface, and is not associated with demonstrable concerns during murine pregnancy. Future studies are required to validate safety and efficacy of CO as a potential therapeutic for vascular insufficiency diseases such as preeclampsia and intrauterine growth restriction.

TDZD-8 alleviates delayed neurological sequelae following acute carbon monoxide poisoning involving tau protein phosphorylation.

Objective: Acute carbon monoxide （CO）poisoning can cause delayed neurological sequelae (DNS). Glycogen synthase kinase 3ß (GSK-3ß) /Tau protein pathway is reported to play a key role in neurological abnormalities. In the present study, we aimed to determine the role of GSK-3ß/Tau in DNS following acute CO poisoning.Methods: 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), a specific non-competitive inhibitor of GSK-3ß, was used to inhibit GSK-3ß. Twenty-four male Sprague-Dawley rats were randomly assigned to the three groups: Control group, CO group and CO-TDZD-8 group. Rats breathed 1000 ppm CO for 40 minutes and then 3000 ppm for up to 20 minutes until they lost consciousness. TDZD-8 (1 mg/kg) was administered intravenously three times after the end of CO exposure at 0, 24, 48 hours late. Learning and memory abilities were observed using the Morris Water Maze (MWM). Brain histological changes were evaluated by hematoxylin-eosin staining. Moreover, the expression levels of Tau and GSK-3ß were detected after acute carbon monoxide poisoning.Results: TDZD-8 significantly attenuated the learning and memory dysfunction induced by acute CO poisoning, ameliorated the histology structure of damaged neural cells in cortex and hippocampus CA1 area. TDZD-8 clearly decreased p-Tau expression, reversed the reduction of p-GSK-3ß induced by acute CO poisoning.Conclusions: The therapeutic effect of TDZD-8 in alleviating DNS caused by acute CO poisoning is related to the inactivation of Tau by intensifying the level of GSK-3ß phosphorylation.

Demographic characteristics and delayed neurological sequelae risk factors in carbon monoxide poisoning.

AIM: Carbon monoxide (CO) is a colorless, odorless gas and tasteless. CO poisoning (COP) is one of the most frequently encountered inhalation poisonings. The most common cause of morbidity in COP is delayed neurological sequelae (DNS). DNS is the occurrence of neuropsychiatric findings within 2-240 days after discharge of patients with COP and there are no definitive diagnostic criteria. The aim of our study is; to determine the risk factors and incidence of DNS. METHOD: Our study is a retrospective, observational study. Patients with the diagnosis of COP in the emergency department between 2015 and 2016 were included in the study. Patients age, gender, findings in the initial physical examination (PE) and neurological examination (NE), blood carboxyhemoglobin (COHb) level, relation between hyperbaric oxygen (HBO) treatment and DNS were assessed. RESULTS: Total of 72 patients were included in the study. Mean age was 33.43 ±â€¯20.89. It was determined that pathological findings in the initial NE are a significant predictive factor for DNS (Odds ratio 18.600, p:0.004). Significant relation between NE and HBO treatment was present (p:00.1). There was no statistically significant relationship between initial COHb level and receiving HBO treatment (p:0.9). Median COHb level of patients with DNS was 30 (min:10, max: 43), median COHb level of patients without DNS was 25 (min:10, max:44) and there was no statistically significant relationship between the two groups according to COHb levels (p:0.7). CONCLUSION: Pathological findings in the initial neurological examination had a predictive value for delayed neurological sequelae in patients with carbon monoxide poisoning.

Effects of hyperbaric oxygen on NLRP3 inflammasome activation in the brain after carbon monoxide poisoning.

Neuroinflammation plays an important role in brain damage after acute carbon monoxide poisoning (ACOP). The nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing (NLRP) 3 inflammasome triggers the activation of inflammatory caspases and maturation of interleukin (IL)-1ß and -18, and has been linked to various human autoinflammatory and autoimmune diseases. In this study we investigated the effects of hyperbaric oxygen (HBO2) on NLRP3 inflammasome activation after ACOP. Mice were randomly divided into four groups: sham group (exposure to normobaric air - i.e., 21% O2 at 1 atmosphere absolute); HBO2-only group; CO + normobaric air group; and CO + HBO2 group. Cognitive function was evaluated with the Morris water maze; myelin injury was assessed by FluoroMyelin GreenTM fluorescent myelin staining and myelin basic protein (MBP) immunostaining; and mRNA and protein levels of NLRP3 inflammasome complex proteins were measured by quantitative real-time PCR and Western blot, respectively. Additionally, serum and brain levels of IL-1ßß and -18 and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase were determined by enzyme-linked immunosorbent assay. It was found that HBO2 improved learning and memory, and alleviated myelin injury in mice subjected to acute CO exposure. Furthermore, HBO2 decreased NLRP3, absent in melanoma 2 (AIM2), caspase-1, and apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain mRNA and protein levels, and reduced brain and serum concentrations of IL-1ß and -18 and NADPH oxidase. These results indicate that HBO2 suppresses the inflammatory response after ACOP by blocking NLRP3 inflammasome activation, thereby alleviating cognitive deficits.

Early white matter injuries associated with dopamine transporter dysfunction in patients with acute CO intoxication: A diffusion kurtosis imaging and Tc-99m TRODAT-1 SPECT study.

PURPOSE: Patients with CO intoxication were demonstrated to exhibit white matter (WM) injuries, changes in substantia nigra, dopamine transporter dysfunctions of striatum and Parkinsonism symptoms. We aimed to investigate the relationship between WM injuries of dopaminergic pathways and dopamine transporter dysfunctions of the striatum in patients with acute CO intoxication using both diffusion kurtosis imaging (DKI) and single photon-emission computed tomography (SPECT). MATERIALS AND METHODS: Seventeen patients with acute CO intoxication and 19 age- and gender-matched healthy subjects were enrolled. DKI data were acquired from all participants and Tc-99m-TRODAT-1 SPECT scan was performed on each patient. DKI datasets were fitted to obtain axial, radial and mean diffusivity, fractional anisotropy, axial, radial and mean kurtosis for voxel-based comparison. In addition, the TRODAT-1 binding ratio of the striatum was calculated using the occipital cortices as a reference. In significant regions, correlational analysis was performed to understand the relationship between DKI indices and TRODAT-1 binding ratio. RESULTS: The results showed that DKI indices were significantly altered in multiple WM regions broadly involving the basal ganglia-thalamocortical circuit and nigrostriatal pathway. The correlation analysis further revealed significant correlations between DKI indices and the TRODAT-1 binding ratio in the nigrostriatal pathway (absolute correlation coefficients ranged from 0.5992 to 0.6950, p<0.05), suggesting that CO-induced early WM injuries were associated with dopamine transporter dysfunctions of striatum. CONCLUSION: We concluded that DKI and Tc-99m-TRODAT-1 SPECT scans were helpful in early detection of global WM injuries associated with dysfunctions of dopamine transporter in patients with acute CO intoxication. KEY POINTS: • Voxel-based diffusion kurtosis imaging analysis was helpful in globally detecting early white matter injuries in patients with acute CO intoxication. • CO-induced early white matter injuries were broadly located in basal ganglia-thalamocortical circuit and nigrostriatal pathway. • Early white matter injuries in dopaminergic pathways were significantly correlated with dopamine transporter dysfunctions of the striatum.

Carboxyhemoglobin half-life during hyperbaric oxygen in a patient with lung dysfunction: a case report.

INTRODUCTION: The carboxyhemoglobin half-life (COHb t1/2) during hyperbaric oxygen (HBO2) is often quoted as 23 minutes, derived from the average of two adult male volunteers breathing HBO2 at 3 atmospheres absolute (ATA). However, the mean COHb t1/2 of 12 male volunteer smokers was 26.3 minutes at 1.58 ATA and in 12 non-intubated carbon monoxide (CO) poisoned patients treated at 3 ATA, was 43 minutes. CASE REPORT: An 81-year old male, poisoned by an improperly ventilated natural gas heater, was intubated for coma, then treated with HBO2. His PaO2/FiO2 = 283 from aspiration. His initial COHb was 34.4%, and 18 minutes before HBO2, 5.9%. After a compression interval of 17 minutes, the COHb measured after 22 minutes at 3 ATA was 3.3%. RESULTS: By exponential decay, his COHb t1/2 before HBO2 was 95 minutes. We estimate the range for COHb t1/2 during compression as 62-81 minutes and for the 3-ATA interval, 58 to 49 minutes, respectively. The mid-point estimate of COHb t1/2 at 3 ATA was 53 minutes. CONCLUSIONS: The COHb t1/2 we calculated is greater than previously reported, but longer in our patient possibly because of concomitant respiratory failure, lung dysfunction, and mechanical ventilation. The often-cited COHb t1/2 of 23 minutes, likely underestimates the actual COHb t1/2 in CO-poisoned patients, especially those with cardiopulmonary dysfunction.

Effects of hyperbaric oxygen on hippocampal neuronal apoptosis in rats with acute carbon monoxide poisoning.

INTRODUCTION: Acute carbon monoxide (CO) poisoning causes serious health problems such as neuropsychological sequelae. This study aimed to investigate neuronal apoptosis and the effects of hyperbaric oxygen (HBO2) on different regions of the rat hippocampus after CO poisoning. METHODS: 90 mature male Sprague Dawley rats were randomly divided into three groups: the normal control group (NC group), the acute carbon monoxide-poisoned group (CO group) and the hyperbaric oxygen treatment group (HBO2 group). CO exposure included 0, 1, 3, 7, 14 and 21 treatment days, one exposure on the first day, and sacrifice on each of the following days. HBO2 exposure included treatment for 0, 1, 3, 7, 14 and 21 days, daily treatment after CO exposure, and sacrifice after the last HBO2 treatment on each of those days. Hematoxylin-eosin staining, immunohistochemical staining, immunofluorescence staining, and western blot analysis were performed to detect apoptosis in brain tissue samples. RESULTS: MMP-9 and caspase-3 were prominently increased by CO exposure and inhibited by HBO2 in the CA3 region in the hippocampus at one, three and seven days (immunohistochemical staining [IHC]: P ⟨ 0.05). Neu N and the ratio of Bcl-2/ BAX were prominently decreased by CO exposure and rescued by HBO2 in the CA3 region after seven days of treatment (IHC: P ⟨ 0.05). CONCLUSION: These findings indicated that neuronal apoptosis in the rat hippocampus could be induced by acute CO exposure, especially in the CA3 region. HBO2 could effectively inhibit neuronal apoptosis, especially in the CA3 region after seven days of treatment. The application of HBO2 to inhibit MMP-9 and apoptosis may contribute to brain recovery after acute CO poisoning.

Modulation of JAK2, STAT3 and Akt1 proteins by granulocyte colony stimulating factor following carbon monoxide poisoning in male rat.

Carbon monoxide (CO) is an odorless, colorless, tasteless and non-irritating by-product of inefficient combustion of hydrocarbon fuels such as motor vehicle exhausted gases. It is the leading cause of mortality in the USA among all unintentional toxicants. Male rats exposed to CO poisoning in the heart has many cardiovascular effects such as, cardiomyopathy, tachycardia, arrhythmias, and ischemia and in severe cases, myocardial infarction (MI) and cardiac arrest. Cardiomyocyte apoptosis is one of the most frequent consequences in the heart. Granulocyte colony stimulating factor (G-CSF) is a cytokine that mobilizes and differentiates granulocytes from stem cells. It can stimulate many anti-apoptotic pathways such as JAK2-STAT3 and PI3-Akt kinases following cardiac ischemia. G-CSF exerts its anti-apoptotic effects through binding to its specific cell surface receptor. The purpose of this study was to elucidate the mechanism of anti-apoptotic effect of G-CSF following CO poisoning. Rats were exposed to CO 1500 or 3000 ppm for 60 min. Animals received G-CSF 100 µg/kg subcutaneously for five consecutive days after CO intoxication. Western blot analysis was used to evaluate the expression of six proteins namely JAK2, p-JAK2, STAT3, p-STAT3, Akt1 and p-Akt1 following G-CSF 100 µg/kg consecutive dose administration after CO poisoning. There was a significant difference between phosphorylated proteins including p-JAK2, p-STAT3 and p-Akt1 in the G-CSF groups and those in control groups and there were not any significant differences in total protein among the groups.

Edaravone attenuates brain damage in rats after acute CO poisoning through inhibiting apoptosis and oxidative stress.

Acute carbon monoxide (CO) poisoning is the most common cause of death from poisoning all over the world and may result in neuropathologic and neurophysiologic changes. Acute brain damage and delayed encephalopathy are the most serious complication, yet their pathogenesis is poorly understood. The present study aimed to evaluate the neuroprotective effects of Edaravone against apoptosis and oxidative stress after acute CO poisoning. The rat model of CO poisoning was established in a hyperbaric oxygen chamber by exposed to CO. Ultrastructure changes were observed by transmission electron microscopy (TEM). TUNEL stain was used to assess apoptosis. Immunohistochemistry and immunofluorescence double stain were used to evaluate the expression levels of heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf-2) protein and their relationship. By dynamically monitored the carboxyhemoglobin (HbCO) level in blood, we successfully established rat model of severe CO poisoning. Ultrastructure changes, including chromatin condensation, cytoplasm dissolution, vacuoles formation, nucleus membrane and cell organelles decomposition, could be observed after CO poisoning. Edaravone could improve the ultrastructure damage. CO poisoning could induce apoptosis. Apoptotic cells were widely distributed in cortex, striatum and hippocampus. Edaravone treatment attenuated neuronal apoptosis as compared with the poisoning group (P < 0.01). Basal expressions of HO-1 and Nrf-2 proteins were found in normal brain tissue. CO poisoning could activate HO-1/Nrf-2 pathway, start oxidative stress response. After the administration of Edaravone, the expression of HO-1 and Nrf-2 significantly increased (P < 0.01). These findings suggest that Edaravone may inhibit apoptosis, activate the Keapl-Nrf/ARE pathway, and thus improve the ultrastructure damage and neurophysiologic changes following acute CO poisoning.

The effect of fatal carbon monoxide poisoning on the equilibria between cell membranes and the electrolyte solution.

The effect of fatal carbon monoxide poisoning on equilibria between cell membranes and surrounding ions was described using a theoretical four-equilibria model. The model was developed to obtain parameters characterizing the interactions between solution ions and erythrocyte or thrombocyte membrane surface. The parameters are the total surface concentrations of both acidic and basic groups C A, C B and their association constants with solution ions K AH, K BOH. These parameters were used to calculate the theoretical values of surface charge density. The model was validated by comparison of these values to experimental data, which were determined from the electrophoretic mobility measurements of the blood cells. The experimental and theoretical surface charge density values agree at pH 2-8, and at higher pH, the deviation was observed.

Correlations among copeptin, ischemia-modified albumin, and the extent of myocardial injury in patients with acute carbon monoxide poisoning.

This study evaluated the relationships among copeptin, ischemia-modified albumin (IMA), and extent of myocardial injury in patients with acute carbon monoxide poisoning (ACOP). A total of 110 patients with different degrees of ACOP were selected as the poisoning group, and 30 healthy individuals as the control group. The levels of troponin I (cTnI), IMA, and copeptin were detected. Based on the presence of complications, the patients were assigned to the complication (26 patients) or non-complication (84 patients) group. Levels of cTnI, IMA, and copeptin were compared among the control, complication, and non-complication groups. Compared with the control group, in the 2 h after admission, the IMA levels decreased and copeptin levels increased in the poisoning group; these changes were more significant in patients with severe ACOP than in those with mild ACOP, and the difference was statistically significant (P < 0.05). There were no differences in the IMA and copeptin levels between the groups 7 days after admission; the cTnI levels increased more significantly in patients with severe ACOP than in patients with mild and moderate ACOP, and the differences were statistically significant (P < 0.05). In the complication group, at 7 days after admission, the IMA levels decreased whereas the copeptin and cTnI levels were significantly higher than in the non-complication group, with a statistically significant difference (P < 0.05). IMA was negatively correlated with copeptin. IMA and copeptin detection is clinically useful in the early diagnosis and prognosis of ACOP-related myocardial injury and in guiding early clinical drug application.

Early Biomarkers in 1H Nuclear Magnetic Resonance Spectroscopy of Striatal Pathological Mechanisms after Acute Carbon Monoxide Poisoning in Rats.

OBJECTIVE: In vivo Proton Magnetic Resonance Spectroscopy (1H-MRS) can be used to evaluate the levels of specific neurochemical biomarkers of pathological mechanisms in the brain. METHODS: We conducted T2-Weighted Magnetic Resonance Imaging (MRI) and 1H-MRS with a 3.0-Tesla animal MRI system to investigate the early microstructural and metabolic profiles in vivo in the striatum of rats following carbon monoxide (CO) poisoning. RESULTS: Compared to baseline, we found significant cortical surface deformation, cerebral edema changes, which were indicated by the unclear gray/white matter border, and lateral ventricular volume changes in the brain. A significant reduction in the metabolite to total creatine (Cr) ratios of N-acetylaspartate (NAA) was observed as early as 1 h after the last CO administration, while the lactate (Lac) levels increased marginally. Both the Lac/Cr and NAA/Cr ratios leveled off at 6 h and showed no subsequent significant changes. In addition, compared to the control, the choline (Cho)/Cr ratio was slightly reduced in the early stages and significantly increased after 6 h. In addition, a pathological examination revealed mild cerebral edema on cessation of the insult and more severe cerebral injury after additional CO poisoning. CONCLUSION: The present study demonstrated that 1H-MRS of the brain identified early metabolic changes after CO poisoning. Notably, the relationship between the increased Cho/Cr ratio in the striatum and delayed neuropsychologic sequelae requires further research.

Carbon monoxide poisoning is prevented by the energy costs of conformational changes in gas-binding haemproteins.

Carbon monoxide (CO) is a product of haem metabolism and organisms must evolve strategies to prevent endogenous CO poisoning of haemoproteins. We show that energy costs associated with conformational changes play a key role in preventing irreversible CO binding. AxCYTcp is a member of a family of haem proteins that form stable 5c-NO and 6c-CO complexes but do not form O(2) complexes. Structure of the AxCYTcp-CO complex at 1.25 Å resolution shows that CO binds in two conformations moderated by the extent of displacement of the distal residue Leu16 toward the haem 7-propionate. The presence of two CO conformations is confirmed by cryogenic resonance Raman data. The preferred linear Fe-C-O arrangement (170 ± 8°) is accompanied by a flip of the propionate from the distal to proximal face of the haem. In the second conformation, the Fe-C-O unit is bent (158 ± 8°) with no flip of propionate. The energetic cost of the CO-induced Leu-propionate movements is reflected in a 600 mV (57.9 kJ mol(-1)) decrease in haem potential, a value in good agreement with density functional theory calculations. Substitution of Leu by Ala or Gly (structures determined at 1.03 and 1.04 Å resolutions) resulted in a haem site that binds CO in the linear mode only and where no significant change in redox potential is observed. Remarkably, these variants were isolated as ferrous 6c-CO complexes, attributable to the observed eight orders of magnitude increase in affinity for CO, including an approximately 10,000-fold decrease in the rate of dissociation. These new findings have wide implications for preventing CO poisoning of gas-binding haem proteins.