Hyperbaric oxygen therapy mobilized circulating stem cells and improved delayed encephalopathy after acute carbon monoxide poisoning with up-regulation of brain-derived neurotrophic factor

Published:January 14, 2021DOI:


      Delayed encephalopathy (DE) is the most severe complication after acute carbon monoxide (CO) poisoning, which seriously affects the outcome of patients and leads to a high disability rate. Prior studies have shown that hyperbaric oxygen (HBO2) therapy is therapeutic for DE due to reducing immune-mediated neuropathology and thus improving cognitive performance.
      In our present perspective study, five DE patients were treated regularly with HBO2 therapy. The mini-mental state examination (MMSE) and Barthel index (BI) were intermittently collected during their hospitalization for mental and physical status evaluation, the peripheral bloods were serially sampled to determine the concentration changes of circulating stem cells, as well as corresponding BDNF and neural markers.
      MMSE and BI showed series of improvements after multiple HBO2 therapies. The CD34+/CD90+ and CD34+/CD133+ dual positive cells, which were categorized as circulating stem cells, were observed an overall up-regulation since the beginning of the DE onset upon the application of HBO2 therapy. Characteristic neurotrophin BDNF, neural markers such as nestin and synaptophysin (SYP) were also up-regulated after exposure of HBO2.
      The application of HBO2 therapy is of significance in improving the cognition of DE patients, along with mobilized circulating stem cells. We primarily infer that the CD34+/CD90+ and CD34+/CD133+ cells were mobilized by HBO2 exposure and have played a positive role in cognition improvement on DE patients by up-regulation of BDNF, nestin and SYP. The altering amount of circulating stem cells mobilized in peripheral blood could be a potential marker on predicting the outcome of DE.



      Delayed encephalopathy (DE), carbon monoxide (CO), hyperbaric oxygen (HBO2), mini-mental state examination (MMSE), Barthel index (BI), Synaptophysin (SYP)
      To read this article in full you will need to make a payment
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The American Journal of Emergency Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Keim L.
        • Koneru S.
        • Ramos V.F.M.
        • Murr N.
        • Hoffnung D.S.
        • Murman D.L.
        • et al.
        Hyperbaric oxygen for late sequelae of carbon monoxide poisoning enhances neurological recovery: case report.
        Undersea Hyperb Med. 2018; 45: 83-87
        • Hsiao C.L.
        • Kuo H.C.
        • Huang C.C.
        Delayed encephalopathy after carbon monoxide intoxication--long-term prognosis and correlation of clinical manifestations and neuroimages.
        Acta Neurol Taiwan. 2004; 13: 64-70
        • Pepe G.
        • Castelli M.
        • Nazerian P.
        • Vanni S.
        • Del Panta M.
        • Gambassi F.
        • et al.
        Delayed neuropsychological sequelae after carbon monoxide poisoning: predictive risk factors in the Emergency Department. A retrospective study.
        Scand J Trauma Resusc Emerg Med. 2011; 19: 16
        • Ide T.
        • Kamijo Y.
        Myelin basic protein in cerebrospinal fluid: a predictive marker of delayed encephalopathy from carbon monoxide poisoning.
        Am J Emerg Med. 2008; 26: 908-912
        • Chambers C.A.
        • Hopkins R.O.
        • Weaver L.K.
        • Key C.
        Cognitive and affective outcomes of more severe compared toless severe carbon monoxide poisoning.
        Brain In J. 2008; 22: 387-395
        • Weaver L.K.
        • Hopkins R.O.
        • Chan K.J.
        • Churchill S.
        • Elliott C.G.
        • Clemmer T.P.
        • et al.
        Hyperbaric oxygen for acute carbon monoxide poisoning.
        N Engl J Med. 2002; 347: 1057-1067
        • Spagnolo F.
        • Costa M.
        • Impellizzeri M.
        • Cardamone R.
        • Falautano M.
        • Martinelli V.
        • et al.
        Delayed hyperbaric oxygen treatment after acute carbon monoxide poisoning.
        J Neurol. 2011; 258: 1553-1554
        • Thom S.R.
        • Taber R.L.
        • Mendiguren I.I.
        • Clark J.M.
        • Hardy K.R.
        • Fisher A.B.
        Delayed neuropsychologic sequelae after carbon monoxide poisoning: prevention by treatment with hyperbaric oxygen.
        Ann Emerg Med. 1995; 25: 474-480
        • Shandley S.
        • Wolf E.G.
        • Schubert-Kappan C.M.
        • Baugh L.M.
        • Richards M.F.
        • Prye J.
        • et al.
        Increased circulating stem cells and better cognitive performance in traumatic brain injury subjects following hyperbaric oxygen therapy.
        Undersea Hyperb Med. 2017; 44: 257-269
        • Feng Z.C.
        • Liu J.
        • Ju R.
        Hyperbaric oxygen treatment promotes neural stem cell proliferation in the subventricular zone of neonatal rats with hypoxic-ischemic brain damage.
        Neural Regen Res. 2013; 8: 1220-1227
        • Mu J.
        • Krafft P.R.
        • Zhang J.H.
        Hyperbaric oxygen therapy promotes neurogenesis: where do we stand?.
        Med Gas Res. 2011; 1: 14
        • Lee Y.S.
        • Chio C.C.
        • Chang C.P.
        • Wang L.C.
        • Chiang P.M.
        • Niu K.C.
        • et al.
        Long course hyperbaric oxygen stimulates neurogenesis and attenuates inflammation after ischemic stroke.
        Mediat Inflamm. 2013; 2013: 512978
        • Zádori A.
        • Agoston V.A.
        • Demeter K.
        • Hádinger N.
        • Várady L.
        • Köhídi T.
        • et al.
        Survival and differentiation of neuroectodermal cells with stem cell properties at different oxygen levels.
        Exp Neurol. 2011; 227: 136-148
        • De Francesco F.
        • Tirino V.
        • Desiderio V.
        • Ferraro G.
        • D’Andrea F.
        • Giuliano M.
        • et al.
        Human CD34+/CD90+ ASCs are capable of growing as sphere clusters, producing high levels of VEGF and forming capillaries.
        PLoS One. 2009; 4e6537
        • Saalbach A.
        • Wetzig T.
        • Haustein U.F.
        • Anderegg U.
        Detection of human soluble Thy-1 in serum by ELISA. Fibroblasts and activated endothelial cells are a possible source of soluble Thy-1 in serum.
        Cell Tissue Res. 1999; 298: 307-315
        • Ma N.
        • Ladilov Y.
        • Moebius J.M.
        • Ong L.
        • Piechaczek C.
        • Dávid A.
        • et al.
        Intramyocardial delivery of human CD133+ cells in a SCID mouse cryoinjury model: bone marrow vs. cord blood-derived cells.
        Cardiovasc Res. 2006; 71: 158-169
        • Ma Q.
        • Geng Y.
        • Wang H.L.
        • Han B.
        • Wang Y.Y.
        • Li X.L.
        • et al.
        High frequency repetitive transcranial magnetic stimulation alleviates cognitive impairment and modulates hippocampal synaptic structural plasticity in aged mice.
        Front Aging Neurosci. 2019; 11: 235
        • Bernd P.
        The role of neurotrophins during early development.
        Gene Expr. 2008; 14: 241-250
        • Lipsky R.H.
        • Marini A.M.
        Brain-derived neurotrophic factor in neuronal survival and behavior-related plasticity.
        Ann N Y Acad Sci. 2007; 1122: 130-143
        • Gómez-Palacio-Schjetnan A.
        • Escobar M.L.
        Neurotrophins and synaptic plasticity.
        Curr Top Behav Neurosci. 2013; 15: 117-136
        • Castrén E.
        • Rantamäki T.
        The role of BDNF and its receptors in depression and antidepressant drug action: reactivation of developmental plasticity.
        Dev Neurobiol. 2010; 70: 289-297
        • Park H.
        • Poo M.M.
        Neurotrophin regulation of neural circuit development and function.
        Nat Rev Neurosci. 2013; 14: 7-23
        • Elmariah S.B.
        • Hughes E.G.
        • Oh E.J.
        • Balice-Gordon R.J.
        Neurotrophin signaling among neurons and glia during formation of tripartite synapses.
        Neuron Glia Biol. 2004; 1: 1-11
        • Ochi S.
        • Abe M.
        • Li C.
        • Mori Y.
        • Ishimaru T.
        • Yoshino Y.
        • et al.
        The nicotinic cholinergic system is affected in rats with delayed carbon monoxide encephalopathy.
        Neurosci Lett. 2014; 569: 33-37
        • Liu W.C.
        • Yang S.N.
        • Wu C.W.
        • Chen L.W.
        • Chan J.Y.
        Hyperbaric oxygen therapy alleviates carbon monoxide poisoning-induced delayed memory impairment by preserving brain-derived neurotrophic factor-dependent hippocampal neurogenesis.
        Crit Care Med. 2016; 44: e25-e39
        • Thom S.R.
        • Bhopale V.M.
        • Fisher D.
        • Zhang J.
        • Gimotty P.
        Delayed neuropathology after carbon monoxide poisoning is immune-mediated.
        Proc Natl Acad Sci U S A. 2004; 101: 13660-13665
        • Wang P.
        • Zeng T.
        • Zhang C.L.
        • Gao X.C.
        • Liu Z.
        • Xie K.Q.
        • et al.
        Lipid peroxidation was involved in the memory impairment of carbon monoxide-induced delayed neuron damage.
        Neurochem Res. 2009; 34: 1293-1298
        • Jurič D.M.
        • Šuput D.
        • Brvar M.
        Hyperbaric oxygen preserves neurotrophic activity of carbon monoxide-exposed astrocytes.
        Toxicol Lett. 2016; 253: 1-6
        • Wu D.
        Neuroprotection in experimental stroke with targeted neurotrophins.
        NeuroRx. 2005; 2: 120-128
        • Keiner S.
        • Witte O.W.
        • Redecker C.
        Immunocytochemical detection of newly generated neurons in the perilesional area of cortical infarcts after intraventricular application of brain-derived neurotrophic factor.
        J Neuropathol Exp Neurol. 2009; 68: 83-93
        • Waterhouse E.G.
        • Xu B.
        New insights into the role of brain-derived neurotrophic factor in synaptic plasticity.
        Mol Cell Neurosci. 2009; 42: 81-89
        • Chen A.
        • Xiong L.J.
        • Tong Y.
        • Mao M.
        The neuroprotective roles of BDNF in hypoxic ischemic brain injury.
        Biomed Rep. 2013; 1: 167-176
        • Liu Z.
        • Chopp M.
        Astrocytes, therapeutic targets for neuroprotection and neurorestoration in ischemic stroke.
        Prog Neurobiol. 2016; 144: 103-120
        • Stewart W.A.
        • Parent J.M.
        • Towner R.A.
        • Dobson H.
        The use of magnetic resonance imaging in the diagnosis of neurological disease.
        Can Vet J. 1992; 33: 585-590
        • Teipel S.J.
        • Grothe M.
        • Lista S.
        • Toschi N.
        • Garaci F.G.
        • Hampel H.
        Relevance of magnetic resonance imaging for early detection and diagnosis of Alzheimer disease.
        Med Clin North Am. 2013; 97: 399-424
        • Parkinson R.B.
        • Hopkins R.O.
        • Cleavinger H.B.
        • Weaver L.K.
        • Victoroff J.
        • Foley J.F.
        • et al.
        White matter hyperintensities and neuropsychological outcome following carbon monoxide poisoning.
        Neurology. 2002; 58: 1525-1532
        • Nah S.
        • Choi S.
        • Kim H.B.
        • Lee J.
        • Lee S.U.
        • Lee Y.H.
        • et al.
        Cerebral white matter lesions on diffusion-weighted images and delayed neurological sequelae after carbon monoxide poisoning: a prospective observational study.
        Diagnostics (Basel). 2020; 10: 698