myelin-basic-protein and Carbon-Monoxide-Poisoning

Delayed neurologic sequelae (DNS) after carbon monoxide (CO) poisoning manifest as a relapse of neurologic deficits. However, the long-term outcome of DNS has not been fully clarified. Myelin basic protein (MBP) levels in the cerebrospinal fluid (CSF) have been reported to be elevated in DNS. However, the precise timing and clinical value of the CSF examination have not been fully evaluated. We aimed to clarify the long-term outcome and the factors predicting the outcome of DNS and to evaluate the utility of CSF-MBP for predicting the development and severity of DNS.. This work was designed as a single-center, prospective, observational study. We graded DNS severity as Grade 1 (consistent independence), Grade 2 (temporary dependence), or Grade 3 (persistent dependence). We analyzed the percentage categorized in each grade and the parameters associated with outcome.. Of 100 patients experiencing acute CO poisoning (median age: 46 years; 69% male), 20 (20%) developed DNS, including six Grade 1 (30%), ten Grade 2 (50%), and four Grade 3 (20%) cases. The Grade 3 patients [median: 77 years; interquartile range (IQR): 76-82] were older than the Grade 1 patients [42; 30-46] (P<0.01); the DNS onset of the Grade 1 patients [median interval after poisoning: 35 days; IQR: 32-56] occurred later than that of the Grade 3 patients [10; 9-13] P<0.001) and the Grade 2 patients [25; 23-27] (P<0.05). The CSF-MBP levels of the DNS patients were higher than those of the non-DNS patients (P<0.0001). The 1-month CSF-MBP levels of the Grade 3 patients were higher than those of the Grade 1 patients (P<0.05); the MBP index, defined as [(Age)×(1-month CSF-MBP)], was higher in the Grade 3 patients than in the Grade 1 patients (P<0.01). Severe DNS were associated with advanced age (>72.5 years), earlier onset (<18 days), higher 1-month CSF-MBP (>252 pg/ml), and higher MBP index (>20.9 year × ng/ml).. Poor DNS outcomes were associated with advanced age and earlier onset. CSF-MBP can serve as a sensitive predictor of both the development and outcomes of DNS.

Topics: Acute Disease; Adult; Age Factors; Aged; Aged, 80 and over; Biomarkers; Carbon Monoxide Poisoning; Female; Humans; Japan; Magnetic Resonance Imaging; Male; Middle Aged; Myelin Basic Protein; Neurotoxicity Syndromes; Predictive Value of Tests; Prognosis; Prospective Studies; Risk Assessment; Risk Factors; Severity of Illness Index; Time Factors; Young Adult

We investigated dexamethasone therapy for preventing delayed encephalopathy after carbon monoxide (CO) poisoning. Eighty healthy male rats were exposed to CO and randomly divided into four groups: hyperbaric oxygen treatment (H), treatment (D), combined hyperbaric and dexamethasone treatment (C), and a control (M) group in which the rats inhaled CO to coma in the hyperbaric oxygen chamber, then were removed without further treatment. Twelve rats were put into the hyperbaric oxygen chamber and treated with air for 60 min (N) group. An eight arm maze was used to evaluate cognitive and memory abilities of these mice. Serum myelin basic protein (MBP) levels were evaluated using ELISA, and magnetic resonance imaging was used to observe brain demyelination and morbidity associated with delayed encephalopathy. A sample of the hippocampus from each group was examined by light microscopy. Cognitive and memory functions decreased in the control group M. Three days after CO poisoning, the serum MBP level of each group increased significantly. On Day 10 after CO poisoning, the MBP levels in groups C and D decreased significantly, but returned to normal on Day 18. MBP levels in the M and H groups were elevated at all time points. Brain MRIs showed significant differences among C, D, H and control M groups. Hematoxylin & eosin staining of the hippocampus showed greater damage in the control M and H groups. Early dexamethasone treatment may be useful for preventing delayed encephalopathy after CO poisoning and may reduce serum MBP levels.

Topics: Animals; Anti-Inflammatory Agents; Brain Diseases; Carbon Monoxide Poisoning; Cognition; Combined Modality Therapy; Dexamethasone; Hippocampus; Hyperbaric Oxygenation; Male; Memory; Myelin Basic Protein; Rats; Rats, Wistar; Treatment Outcome

Erythropoietin (EPO) plays a critical role in the development of the nervous system. In this study, the effects of EPO in carbon monoxide (CO) neurotoxicity were examined. Rats were exposed to 3000 ppm CO for 1 h and then different doses of EPO were administrated intraperitoneally. After 24 h, glial fibrillary acidic protein (GFAP) levels in the serum were determined and water content of brain and the extravasation of a tracer (Evans blue) were measured. Brain lipid peroxidation, myeloperoxidase activity Myelin basic protein (MBP) and BAX/BcL2 protein relative expressions were determined. Cation exchange chromatography was used to evaluate MBP alterations. Seven days after exposure, pathological assessment was performed after Klüver-Barrera staining. EPO reduced malondialdehyde levels at all doses (2500, 5000 and 10,000 u/kg). Lower doses of EPO (625, 1250, 2500 u/kg) significantly decreased the elevated serum levels of GFAP. EPO could not reduce the water content of the edematous poisoned brains. However, at 5000 and 10,000 u/kg it protected the blood brain barrier against integrity loss as a result of CO. EPO could significantly decrease the MPO activity. CO-mediated oxidative stress caused chemical alterations in MBP and EPO could partially prevent these biochemical changes. Fewer vacuoles and demyelinated fibers were found in the EPO-treated animals. EPO (5000 u/kg) could restore the MBP density. CO increased brain BAX/Bcl-2 ratio 38.78%. EPO reduced it 38.86%. These results reveal that EPO could relatively prevent different pathways of neurotoxicity by CO poisoning and thus has the potential to be used as a novel approach to manage this poisoning.

Topics: Animals; bcl-2-Associated X Protein; Blood-Brain Barrier; Brain; Carbon Monoxide; Carbon Monoxide Poisoning; Central Nervous System Diseases; Dose-Response Relationship, Drug; Erythropoietin; Gene Expression Regulation; Lipid Peroxidation; Male; Myelin Basic Protein; Proto-Oncogene Proteins c-bcl-2; Random Allocation; Rats; Rats, Wistar

Topics: Acute Disease; Adult; Aged; Biomarkers; Carbon Monoxide Poisoning; Cytokines; Female; Humans; Male; Middle Aged; Myelin Basic Protein; Neurotoxicity Syndromes; Prognosis; S100 Calcium Binding Protein beta Subunit

We aimed to investigate the potential mechanism (s) of delayed encephalopathy after acute carbon monoxide (CO) poisoning in rats, and the effect of dexamethasone on this process. A delayed encephalopathy animal model was generated by intraperitoneal injection of CO into Wistar rats. Normal rats were sent as a control group, and poisoning rats were randomly separated into two groups treated with vehicle and dexamethasone respectively. The rat behavior was evaluated by Morris water maze. The level of myelin basic protein (MBP), myeloperoxidase (MPO) expression in the serum and hippocampus of experimental rats was measured using enzyme-linked immunosorbent assay (ELISA) and immunohisto chemistry. The latency to find the platform was significantly increased by dexamethasone treatment for rats after poisoning at day 7 and 14. MBP serum concentration in the vehicle treatment group was significantly higher than that in rats injected with dexamethasone following poisoning at 90 min, 7d, 14d, 21d. Moreover, MPO concentration was higher at day 14 after poisoning as well. In addition, MBP expression was down regulated in the poisoning group, which was nearly reversed at control level in the dexamethasone group. Inflammation plays a key role in delayed encephalopathy of rats induced by acute CO intoxication, which could be attenuated by dexamethasone via protecting myelin from damage of inflammation response.

Topics: Animals; Brain Diseases; Carbon Monoxide Poisoning; Dexamethasone; Male; Maze Learning; Myelin Basic Protein; Peroxidase; Rats; Rats, Wistar

The present study aimed to detect the main regions of cerebral white matter (CWM) showing damage in the subacute phase for CO-poisoned patients with chronic neurological symptoms using voxel-based analysis (VBA) with diffusion tensor imaging (DTI).. Subjects comprised 22 adult CO-poisoned patients and 16 age-matched healthy volunteers as controls. Patients were classified into patients with transient acute symptoms only (group A) and patients with chronic neurological symptoms (group S). In all patients, DTI covering the whole brain was performed with a 3.0-T magnetic resonance imaging system at 2 weeks after CO exposure. As procedures for VBA, all fractional anisotropy (FA) maps obtained from DTI were spatially normalized, and FA values for all voxels in the whole CWM on normalized FA maps were statistically compared among the two patient groups and controls.. Voxels with significant differences in FA were detected at various regions in comparisons between groups S and A and between group S and controls. In these comparisons, more voxels were detected in deep CWM, including the centrum semiovale, than in other regions. A few voxels were detected between group A and controls. Absolute FA values in the centrum semiovale were significantly lower in group S than in group A or controls.. VBA demonstrated that CO-poisoned patients with chronic neurological symptoms had already suffered damage to various CWM regions in the subacute phase. In these regions, the centrum semiovale was suggested to be the main region damaged in the subacute phase after CO inhalation.

Topics: Adult; Anisotropy; Carbon Monoxide Poisoning; Case-Control Studies; Cerebral Cortex; Diffusion Tensor Imaging; Female; Glasgow Coma Scale; Humans; Image Interpretation, Computer-Assisted; Male; Middle Aged; Myelin Basic Protein; Statistics, Nonparametric

Carbon monoxide (CO) poisoning leads to demyelination of cerebral white matter (CWM) fibers, causing chronic neuropsychiatric symptoms. To clarify whether fractional anisotropy (FA) from diffusion tensor imaging in the centrum semiovale can depict demyelination in the CWM during the subacute phase after CO inhalation, we examined correlations between FA in the centrum semiovale and myelin basic protein (MBP) in cerebrospinal fluid. Subjects comprised 26 adult CO-poisoned patients ≤60 years old. MBP concentration was examined for all patients at 2 weeks after CO inhalation. The mean FA of the centrum semiovale bilaterally at 2 weeks was also examined for all patients and 21 age-matched healthy volunteers as controls. After these examinations, the presence of chronic symptoms was checked at 6 weeks after CO poisoning. Seven patients displayed chronic symptoms, of whom six showed abnormal MBP concentrations. The remaining 19 patients presented no chronic symptoms and no abnormal MBP concentrations, with MBP concentrations undetectable in 16 patients. The MBP concentration differed significantly between patients with and without chronic symptoms. The mean FA was significantly lower in patients displaying chronic symptoms than in either patients without chronic symptoms or controls. After excluding the 16 patients with undetectable MBP concentrations, a significant correlation was identified between MBP concentration and FA in ten patients. The present results suggest that FA in the centrum semiovale offers a quantitative indicator of the extent of demyelination in damaged CWM during the subacute phase in CO-poisoned patients.

Topics: Adult; Anisotropy; Biomarkers; Carbon Monoxide Poisoning; Cerebrum; Diffusion Tensor Imaging; Female; Humans; Male; Middle Aged; Myelin Basic Protein; Nerve Fibers, Myelinated; Pyramidal Tracts; Young Adult

There is structural damage to myelin and secondary immune injury in the development of delayed encephalopathy after acute carbon monoxide (CO) poisoning (DEACMP). In order to assess the role of genetic factors in this mechanism, we studied the association between tumor necrosis factor-α308 (TNF-α308) and myelin basic protein (MBP) 5'-side tetranucleotide repetitive sequence (TGGA) n gene polymorphism and DEACMP. We selected 109 DEACMP patients from the Han population in the Northern Henan Province as the case group, and 115 patients without delayed encephalopathy (called the acute CO poisoning group or the control group). There were no significant differences in TNF-α308 and MBP 5'-side TGGA n genotype distribution and allele frequency between the DEACMP group and the acute CO poisoning group (all P > 0.05). When the population was stratified by gender, only the MBP 5'-side TGGA n allele frequency was significantly different, and the frequency of allele L in the DEACMP group was significantly higher than that of the acute CO poisoning group in males (χ(2) = 4.089, P = 0.043, odds ratio = 2.103, 95% confidence interval = 1.014-4.363). The results showed that there was association between MBP 5'-side TGGA n gene polymorphism and DEACMP, and that allele L could increase the risk of occurrence in male patients with DEACMP. DEACMP may be the result of interaction of environmental and genetic factors.

Topics: Adult; Aged; Aged, 80 and over; Base Sequence; Carbon Monoxide Poisoning; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Myelin Basic Protein; Neurotoxicity Syndromes; Polymorphism, Genetic; Tumor Necrosis Factor-alpha

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Carbon Monoxide Poisoning; Female; Humans; Interleukin-6; Male; Middle Aged; Myelin Basic Protein; Neurotoxicity Syndromes; Prospective Studies; Young Adult

We investigated the feasibility and efficacy of hydrogen-rich saline therapy on delayed neurologic sequelae in a rat model of severe acute carbon monoxide (CO) poisoning.. Controlled animal study.. University research laboratory for Diving Medicine.. Sprague-Dawley rats weighing 250 ± 20 g.. The rats were exposed to 1000 ppm CO in air for 40 min and then to 3000 ppm for another 20 min until they lost consciousness. Rats were intraperitoneal injected with hydrogen-rich saline or normal saline (10 mL/kg) for six times after resuscitation at 0, 12, 24, 36, 48, and 60 hrs, respectively. The rats without CO poisoning were used as normal controls.. Brain tissue inflammation, cell death, and cognitive dysfunction were observed at one week after CO poisoning. Hydrogen-rich saline treatment significantly reduced the level of degraded myelin basic protein, decreased the expression of ionized calcium-binding adapter molecule 1, Iba1, a microglial marker, reduced DNA oxidation, and suppressed proinflammatory cytokine interleukin-1β, interleukin-6, and tumor necrosis factor-α in the cortex and hippocampal tissues when compared with those in normal saline-treated rats. These histologic and biological improvements were accompanied with an improvement in the Morris water maze test.. This observation demonstrated that hydrogen-rich saline peritoneal injection improves histologic and functional assessment in a rat model of CO encephalopathy. Hydrogen saline has potentials as a novel and alternative therapy for severely CO-poisoned patients with delayed neurologic sequelae. The therapeutic effects of hydrogen-rich saline may be related to antioxidant and anti-inflammatory actions.

Topics: Animals; Brain; Brain Chemistry; Calcium-Binding Proteins; Carbon Monoxide Poisoning; Cerebral Cortex; Hippocampus; Hydrogen; Inflammation; Interleukin-1beta; Interleukin-6; Male; Maze Learning; Microfilament Proteins; Myelin Basic Protein; Rats; Rats, Sprague-Dawley; Sodium Chloride; Tumor Necrosis Factor-alpha

The authors examined whether (1)H-magnetic resonance spectroscopy (MRS) can identify damage to the centrum semiovale in the subacute phase after CO exposure.. Subjects comprised 29 adult patients who were treated with hyperbaric oxygenation within a range of 4-95 h (mean 18.7 h) after CO exposure. Subjects were classified into three groups according to clinical behaviours: Group A, patients with transit acute symptoms only; Group P, patients with persistent neurological symptoms; and Group D, patients with 'delayed neuropsychiatric sequelae' occurring after a lucid interval. MRS of bilateral centrum semiovale was performed 2 weeks after CO inhalation for all patients and 13 healthy volunteers. The mean ratios of choline-containing compounds/creatine ((mean)Cho/Cr) and N-acetylaspartate/Cr ((mean)NAA/Cr) for bilateral centrum semiovale were calculated and compared between the three CO groups and controls. Myelin basic protein (MBP) concentration in cerebrospinal fluid was examined at 2 weeks to evaluate the degree of demyelination in patients.. MBP concentration was abnormal for almost all patients in Groups P and D, but was not abnormal for any Group A patients. The (mean)Cho/Cr ratios were significantly higher in Groups P and D than in Group A. No significant difference in (mean)NAA/Cr ratio was seen between the three pathological groups and controls. A significant correlation was identified between MBP and (mean)Cho/Cr ratio.. These results suggest that the Cho/Cr ratio in the subacute phase after CO intoxication represents early demyelination in the centrum semiovale, and can predict chronic neurological symptoms.

Topics: Brain; Brain Diseases, Metabolic; Carbon Monoxide Poisoning; Choline; Creatine; Demyelinating Diseases; Female; Follow-Up Studies; Humans; Hyperbaric Oxygenation; Magnetic Resonance Spectroscopy; Male; Middle Aged; Myelin Basic Protein; Nerve Fibers, Myelinated; Protons; Time Factors

The neurotoxicity of carbon monoxide (CO) poisoning is a significant clinical problem, but its mechanisms remain unclear. Previous studies of CO-exposed rats showed spatial memory disturbances and degradation of myelin basic protein (MBP) in the brain; however, regional localization of the degradation was not analyzed. In the present study, we histologically determined the foci of CO effects in the hippocampus. Wistar rats were exposed to CO for 60min (1000ppm for 40min+3000ppm for 20min) and returned into room air. For histological evaluation, the animals were sacrificed 90min, 1, 7 and 14 days after CO exposure and the brain tissue was analyzed with hematoxylin-eosin (HE), Nissl and Gallyas myelin staining as well as immunohistochemistry for MBP and phosphorylated or nonphosphorylated neurofilament. No histological changes were observed on HE, Nissl or Gallyas staining. In contrast, we detected MBP reduction at 90min after CO exposure in the dentate gyrus and CA3, and the recovery of MBP was observed after 14 days. The immunoreactivity of neurofilament also changed after CO exposure. Nevertheless, water maze test showed no significant effects of CO exposure on spatial memory. Our findings demonstrate that CO poisoning causes transient degradation of MBP and axonal injury in the hippocampus even though the animals showed no neurological disturbances.

Topics: Animals; Blotting, Western; Carbon Monoxide; Carbon Monoxide Poisoning; Hippocampus; Immunohistochemistry; Maze Learning; Myelin Basic Protein; Neurons; Rats; Rats, Wistar; Statistics, Nonparametric; Time Factors

This study was designed to investigate whether interleukin 6 (IL-6) in cerebrospinal fluid (CSF) in the early phase of carbon monoxide (CO) poisoning can be a predictive marker of delayed encephalopathy (DE).. Nine patients with CO poisoning were included in the study. Cerebrospinal fluid was sampled within 24 hours of the last exposure to CO, on hospital day 4, and once a week for at least 1 month to determine IL-6 and myelin basic protein concentrations. All patients were followed at least 3 months.. Three patients demonstrated significant early IL-6 elevation in CSF, normal IL-6 level in CSF on day 4, and significant delayed myelin basic protein elevation in CSF. The 2 patients with the highest early IL-6 elevation in CSF developed DE. Interleukin 6 in serum was not related to DE.. Interleukin 6 in CSF at the early phase of CO poisoning may be a predictive marker of DE.

Topics: Adult; Aged; Biomarkers; Carbon Monoxide Poisoning; Female; Humans; Interleukin-6; Male; Middle Aged; Myelin Basic Protein; Neurotoxicity Syndromes; Predictive Value of Tests

This study was designed to investigate whether myelin basic protein (MBP) in cerebrospinal fluid (CSF) can be a predictive marker of delayed encephalopathy from carbon monoxide (CO) poisoning. Five patients with CO poisoning were included in the study. The CSF was serially sampled to determine the MBP concentration. All patients were classified into group DE or group non-DE according to whether delayed encephalopathy developed or not. In all 3 patients in group DE, the MBP levels in the CSF were markedly elevated preceding the clinical manifestations of delayed encephalopathy. In both group non-DE patients, the MBP concentrations in the CSF were never elevated. Elevated MBP concentrations in the CSF may represent a predictive marker of delayed encephalopathy from CO poisoning, leading to a more appropriate triage of patients with CO poisoning.

Topics: Adult; Biomarkers; Carbon Monoxide Poisoning; Enzyme-Linked Immunosorbent Assay; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Myelin Basic Protein; Neurotoxicity Syndromes; Predictive Value of Tests; Prospective Studies

Neurological sequelae (NS) is a common complication of carbon monoxide (CO) poisoning and structural alterations of myelin basic protein have been proven to initiate immunological reactions leading to NS. To determine whether xanthine oxidoreductase (XOR) participates in the pathophysiology of CO-mediated NS, we examined myelin basic protein in CO poisoned XOR-depleted rats and performed radial maze studies to evaluate the alteration of cognitive function. Carbon monoxide poisoned XOR-depleted rats did not exhibit myelin basic protein alterations or impaired cognitive function, both found in CO poisoned control rats. These results indicate that XOR is essential to the pathological cascade of CO-mediated NS.

Topics: Animals; Brain; Carbon Monoxide; Carbon Monoxide Poisoning; Cognition Disorders; Male; Maze Learning; Myelin Basic Protein; Rats; Rats, Wistar; Xanthine Dehydrogenase

Topics: Adult; Biomarkers; Carbon Monoxide Poisoning; Female; Humans; Hypoxia, Brain; Myelin Basic Protein; Predictive Value of Tests; Recurrence; Treatment Outcome

The goal of this investigation was to determine whether exposure to hyperbaric oxygen (HBO(2)) would ameliorate biochemical and functional brain abnormalities in an animal model of carbon monoxide (CO) poisoning. In this model, CO-mediated oxidative stress causes chemical alterations in myelin basic protein (MBP), which initiates an adaptive immunological response that leads to a functional deficit. CO-exposed rats do not show improvements in task performance in a radial maze. We found that HBO(2) given after CO poisoning will prevent this deficit, but not eliminate all of the CO-mediated biochemical alterations in MBP. MBP from HBO(2) treated CO-exposed rats is recognized normally by a battery of antibodies, but exhibits an abnormal charge pattern. Lymphocytes from HBO(2)-treated and control rats do not become activated when incubated with MBP, immunohistological evidence of microglial activation is not apparent, and functional deficits did not occur, unlike untreated CO-exposed rats. The results indicate that HBO(2) prevents immune-mediated delayed neurological dysfunction following CO poisoning.

Topics: Animals; Brain; Carbon Monoxide Poisoning; Central Nervous System Diseases; Disease Models, Animal; Hyperbaric Oxygenation; Male; Maze Learning; Myelin Basic Protein; Neurons; Oxidative Stress; Oxygen; Rats; Rats, Wistar

Topics: Acute Disease; Carbon Monoxide Poisoning; Cerebral Cortex; Cerebral Hemorrhage; Cerebral Infarction; Diffusion Magnetic Resonance Imaging; Globus Pallidus; Humans; Iron; Myelin Basic Protein; Nerve Fibers, Myelinated; Prospective Studies

The neuropathological sequelae of carbon monoxide (CO) poisoning cannot be explained by hypoxic stress alone. CO poisoning also causes adduct formation between myelin basic protein (MBP) and malonylaldehyde, a reactive product of lipid peroxidation, resulting in an immunological cascade. MBP loses its normal cationic characteristics, and antibody recognition of MBP is altered. Immunohistochemical evidence of degraded MBP occurs in brain over days, along with influx of macrophages and CD-4 lymphocytes. Lymphocytes from CO-poisoned rats subsequently exhibit an auto-reactive proliferative response to MBP, and there is a significant increase in the number of activated microglia in brain. Rats rendered immunologically tolerant to MBP before CO poisoning exhibit acute biochemical changes in MBP but no lymphocyte proliferative response or brain microglial activation. CO poisoning causes a decrement in learning that is not observed in immunologically tolerant rats. These results demonstrate that delayed CO-mediated neuropathology is linked to an adaptive immunological response to chemically modified MBP.

Topics: Animals; Brain; Carbon Monoxide; Carbon Monoxide Poisoning; Cognition Disorders; Hydrogen-Ion Concentration; Immunohistochemistry; Lymphocyte Activation; Lymphocytes; Male; Malondialdehyde; Maze Learning; Microglia; Myelin Basic Protein; Neurons; Protein Isoforms; Rats; Rats, Wistar