Abstract
Delayed neurologic sequelae (DNS) are recurrent–transient neuropsychiatric consequences of carbon monoxide (CO) intoxication. Pathologically DNS features damages to the brain white matter. Here we test a hypothesis that direct cytotoxicity of CO to oligodendrocytes plays a role in the development of DNS. In an in vitro model of CO poisoning with the carbon monoxide releasing molecule-2 (CORM-2) as a CO donor, we show that CORM-2 at concentrations higher than 200 µM significantly inhibited viability and caused significant death of PC12 cells. Similar minimum toxicity concentration was observed on primary brain cells including neurons, astrocytes, and microglia. Interestingly, oligodendrocytes showed cytotoxicity to CORM-2 at a much lower concentration (100 µM). We further found that CORM-2 at 100 µM inhibited proteolipid protein (PLP) production and reduced myelin coverage on axons in an in vitro model of myelination. Our results show that direct cytotoxicity is a mechanism of CO poisoning and DNS may result from a high susceptibility of oligodendrocytes to CO poisoning.
Highlights
Carbon monoxide (CO) poisoning is one of the leading causes of death and injury worldwide [1]
Our results show that direct cytotoxicity is a mechanism of CO poisoning and delayed neurological sequelae (DNS) may result from a high susceptibility of oligodendrocytes to CO poisoning
The present study provides evidence for direct cytotoxicity of carbon monoxide released from carbon monoxide releasing molecule-2 (CORM-2)
Summary
Carbon monoxide (CO) poisoning is one of the leading causes of death and injury worldwide [1]. Acute symptoms of CO poisoning are non-specific and varied but are mainly associated with the brain and heart, including headache, fatigue, malaise, “trouble thinking”, confusion, nausea, dizziness, visual disturbances, chest pain, shortness of breath, loss of consciousness, and seizures. Because the brain and the heart have a high demand for oxygen, these acute symptoms are believed to be resulted from CO-induced hypoxia due to the formation of carboxyhemoglobin (COHb), which is over 200-fold more stable than oxyhemoglobin (O2Hb) [2, 3]. Up to a third of survivors develop delayed neurological sequelae (DNS) within weeks after an initial complete clinical recovery from acute poisoning. Most frequently described sequelae include a broad spectrum of neurological deficits, cognitive impairments, and affective disorders. DNS gradually resolves over the first months but can be permanent in about 25% of cases.
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