OBJECTIVES: The neurotoxicity of carbon monoxide (CO) to the central nervous system is a key pathogenesis of delayed encephalopathy after acute carbon monoxide poisoning (DEACMP). Our previous study found that retinoic acid (RA) can suppress the neurotoxic effects of CO. This study further explores, in vivo and in vitro, the molecular mechanisms by which RA alleviates CO-induced central nervous system damage. METHODS: A cytotoxic model was established using the mouse hippocampal neuronal cell line HT22 and primary oligodendrocytes exposed to CO, and a DEACMP animal model was established in adult Kunming mice. Cell viability and apoptosis of hippocampal neurons and oligodendrocytes were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Annexin V/propidium iodide (PI) double staining. The transcriptional and protein expression of each gene was detected using real-time fluorescence quantitative PCR (RT-qPCR) and Western blotting. Long noncoding RNA (lncRNA) SNHG15 and LINGO-1 were knocked down or overexpressed to observe changes in neurons and oligodendrocytes. In DEACMP mice, SNHG15 or LINGO-1 were knocked down to assess changes in central nervous tissue and downstream protein expression. RESULTS: RA at 10 and 20 μmol/L significantly reversed CO-induced apoptosis of hippocampal neurons and oligodendrocytes, downregulation of SNHG15 and LINGO-1, and upregulation of brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB) (all P<0.05). Overexpression of SNHG15 or LINGO-1 weakened the protective effect of RA against CO-induced cytotoxicity (all P<0.05). Knockdown of SNHG15 or LINGO-1 alleviated CO-induced apoptosis of hippocampal neurons and oligodendrocytes and upregulated BDNF and TrkB expression levels (all P<0.05). Experiments in DEACMP model mice showed that knockdown of SNHG15 or LINGO-1 mitigated central nervous system injury in DEACMP (all P<0.05). CONCLUSIONS RA alleviates CO-induced apoptosis of hippocampal neurons and oligodendrocytes, thereby reducing central nervous system injury and exerting neuroprotective effects. LncRNA SNHG15 and LINGO-1 are key molecules mediating RA-induced inhibition of neuronal apoptosis and are associated with the BDNF/TrkB pathway. These findings provide a theoretical framework for optimizing the clinical treatment of DEACMP and lay an experimental foundation for elucidating its molecular mechanisms.
Animals ; RNA, Long Noncoding/physiology* ; Brain-Derived Neurotrophic Factor/genetics* ; Carbon Monoxide Poisoning/complications* ; Mice ; Tretinoin/pharmacology* ; Nerve Tissue Proteins/metabolism* ; Membrane Proteins/metabolism* ; Apoptosis/drug effects* ; Hippocampus/cytology* ; Receptor, trkB/metabolism* ; Neurons/drug effects* ; Male ; Brain Diseases/etiology* ; Oligodendroglia/drug effects* ; Signal Transduction ; Cell Line

The organosulfur compound sulforaphane (SFN; C₆H₁₁NOS₂) is a potent cytoprotective agent promoting antioxidant, anti-inflammatory, antiglycative, and antimicrobial effects in in vitro and in vivo experimental models. Mitochondria are the major site of adenosine triphosphate (ATP) production due to the work of the oxidative phosphorylation (OXPHOS) system. They are also the main site of reactive oxygen species (ROS) production in nucleated human cells. Mitochondrial impairment is central in several human diseases, including neurodegeneration and metabolic disorders. In this paper, we describe and discuss the effects and mechanisms of action by which SFN modulates mitochondrial function and dynamics in mammalian cells. Mitochondria-related pro-apoptotic effects promoted by SFN in tumor cells are also discussed. SFN may be considered a cytoprotective agent, at least in part, because of the effects this organosulfur agent induces in mitochondria. Nonetheless, there are certain points that should be addressed in further experiments, indicated here as future directions, which may help researchers in this field of research.
Animals ; Antioxidants/pharmacology* ; Apoptosis/drug effects* ; Brain/ultrastructure* ; Carbon Monoxide Poisoning/metabolism* ; Cytoprotection ; Humans ; Isothiocyanates/pharmacology* ; Membrane Potential, Mitochondrial/drug effects* ; Mitochondria/metabolism* ; Sulfoxides

OBJECTIVEIn vivo Proton Magnetic Resonance Spectroscopy (1H-MRS) can be used to evaluate the levels of specific neurochemical biomarkers of pathological mechanisms in the brain.

METHODSWe 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.

RESULTSCompared 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.

CONCLUSIONThe 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.

Animals ; Biomarkers ; Carbon Monoxide Poisoning ; metabolism ; Corpus Striatum ; drug effects ; metabolism ; Magnetic Resonance Spectroscopy ; methods ; Male ; Rats ; Rats, Sprague-Dawley

OBJECTIVE: To explore the expression of tryptase and chymase in human lung tissue of anaphylactic shock and its value for forensic medicine. METHODS: With ten carbon monoxide poisoning cases as control group, the levels of tryptase and chymase were observed by immunofluorescence and analyzed using the Image Analyze and the Image-pro plus 5.0.2. The positive mast cells were counted and the levels of the tryptase and chymase were calculated respectively. RESULTS: There was a statistically significant difference (P < 0.05) for the tryptase and chymase concentrations in the lung tissue between the anaphylactic shock group and the control group. CONCLUSION The levels of the tryptase and the chymase expression are greatly increased in human lung tissue of anaphylactic shock, which may provide the morphological evidence and reference for the diagnosis of anaphylactic shock in forensic practice.
Adolescent ; Adult ; Anaphylaxis/pathology* ; Cadaver ; Carbon Monoxide Poisoning/pathology* ; Child ; Child, Preschool ; Chymases/metabolism* ; Female ; Fluoroimmunoassay/methods* ; Forensic Pathology ; Humans ; Infant ; Lung/pathology* ; Male ; Mast Cells/enzymology* ; Middle Aged ; Staining and Labeling ; Tryptases/metabolism* ; Young Adult

Acute Disease ; Carbon Monoxide Poisoning ; enzymology ; physiopathology ; Creatine Kinase ; metabolism ; Creatine Kinase, MB Form ; Echocardiography ; Heart ; physiopathology ; Humans ; Hyperbaric Oxygenation ; Isoenzymes ; metabolism ; Myocardium ; enzymology

Acute carbon monoxide (CO) poisoning primarily affects the central nervous system(CNS), and survivors of severe CO poisoning often suffer permanent neuropsychiatric sequelae. The most widely recognized long-term sequelae of acute CO poisoning are neurobehavioral abnormalities varying from mild personality changes, difficulty in learning and behavioral problems, to irreversible dementia. The mechanisms of these processes are poorly understood although same investigators have suggested the involvement of CO-mediated brain cerebral mitochondrial energy metabolism. Since cellular injury by almost any mechanism has the potential to accelerate free radical reactions, it appears that reactive oxygen species (ROS) may have a critical role in CO-induced brain injury. There is evidence in rats that CO vulnerable brain regions show increased production of hydrogen peroxide and hydroxyl radical after acute poisoning. On the other hand, recent evidence suggests that the novel free radical neuromodulator, nitric oxide (NO), mediates NMDA receptor-linked excitotoxicity, and that neurons that contain NO synthase (NOS) are themselves spared from NMDA and NO toxic effects. NADPH-diaphorase neurons preferentially survive in the striatum in patients with Huntington's disease, Alzheimer's disease, and relatively spared in experimental models of brain damage due to ischemia or NMDA-mediated neurotoxins. In contrast to these findings, current experiment revealed that some of NOS neuons underwent degenerative changes several days after CO exposure. Moreover, oxidative stress itself could be a mediator of apoptosis much as programmed cell death associated with experimental focal cerebral ischemia in rats. Likewise apoptosis after CO poisoning might be a cause of cell death in addition to conventional necrotic cell death. Subsequent studies are needed to verify this conjecture, which eventually can elucidate the 'biphasic' clinical features of CO poisoning.
Alzheimer Disease ; Animals ; Apoptosis ; Brain Injuries ; Brain Ischemia ; Brain* ; Carbon Monoxide Poisoning* ; Carbon Monoxide* ; Carbon* ; Cell Death ; Dementia ; Energy Metabolism ; Hand ; Humans ; Huntington Disease ; Hydrogen Peroxide ; Hydroxyl Radical ; Ischemia ; Learning ; Models, Theoretical ; N-Methylaspartate ; Neurons* ; Neurotoxins ; Neurotransmitter Agents ; Nitric Oxide Synthase* ; Nitric Oxide* ; Oxidative Stress ; Poisoning ; Rats* ; Reactive Oxygen Species ; Research Personnel ; Survivors

Delayed hypoxic encephalopathy is one of the most important neurologic sequelae in carbon monoxide (CO) poisoning. Regional cerebral blood flow (CBF) of cerebral cortices were measured in five patients with delayed CO encephalo'pathy confirmed by clinical features and magnetic resonance imaging (MRI) and five normal persons using "'Tc-HMPAO SPECT (technetium 99m hexamethylpropylene amine oxide single photon emission computed tomography). For the quantitative analysis, six pairs of region of interest in cerebral cortices and cerebellar hemispheres were determined. Among five regions to cerebellar ratios, those of superior and inferior frontal, parietal, and temporal cortices were significantly reduced (p<005). The degree of reduction in CBF was marked especially in frontal and temporal cortices and similar in both hemispheres. Early scan failed to predict delayed neurologic sequelae in one patient, but follow-up scan was well correlated with clinical improvement in another patient. Diffuse reduction of CBF in cerebral cortices was different from the anatomical MR findings. We think that reduced CBF in cerebral cortices is associated with clinical features of delayed carbon monoxide encephalopathy. Transient vascular mechan' ism or re duced cortical energy metabolism might be the cause of reduced CBF in cerebral cortices.
Carbon Monoxide* ; Carbon* ; Cerebral Cortex ; Energy Metabolism ; Follow-Up Studies ; Humans ; Hypoxia, Brain ; Magnetic Resonance Imaging ; Poisoning ; Rabeprazole ; Tomography, Emission-Computed, Single-Photon

We studied the effect of carbon monoxide (CO)-induced hypoxia on synaptosomal uptake and release of dopamine (DA) in rat striatum. When the rats were intoxicated at a blood level of carboxyhemoglobin (HbCO), 60-70% for 3-4hrs, [3H] DA uptake was inhibited as much as 80% of control activity. This suppressed activity remained as long as 12 hrs after termination of the intoxication. After a week recovery period, the suppressed uptake activity was restored completely. When the rats were intoxicated maintaining a blood level of HbCO at 30-40% for 6-7hrs, the uptake was inhibited to 57% of the control actvity and this suppressed activity was restored within 12hrs. For the rats maintaining a blood level of HbCO at 15-25% for 6-7hrs, uptake inhibition was not shown. Acute CO intoxication(at 60-70% of HbCO for 3-4 hrs) caused an increase in K+-stimulated DA release to 147% of the control value. In conclusion, the diminished uptake and increased release of striatal DA in a CO intoxicated brain would cause an extraneuronal accumulation of DA with depletion of intraneuronal DA level, which may play a role in CO-induced hypoxic cell damage.
Animal ; Carbon Monoxide Poisoning/*complications ; Corpus Striatum/*ultrastructure ; Culture Media ; Dopamine/*metabolism ; Female ; Hypoxia, Brain/chemically induced/*pathology ; In Vitro ; Male ; Rats ; Synaptosomes/*metabolism