Oligodendrocyte dysfunction and regeneration failure: A novel hypothesis of delayed encephalopathy after carbon monoxide poisoning

Abstract Carbon monoxide (CO) poisoning usually causes brain lesions and delayed encephalopathy, also known as delayed neurological sequelae (DNS). Demyelination of white matter (WM) is one of the most common sites of abnormalities in patients with DNS, but its mechanisms remain unclear. Oligodendrocytes (OLs) are myelinated cells that ensure the rapid conduction of neuronal axon signals and provide the nutritional factors necessary for maintaining nerve integrity in the central nervous system (CNS). OLs readily regenerate and replace damaged myelin membranes around axons in the adult mammalian CNS following demyelination. The ability to regenerate OLs depends on the availability of precursor cells (OPCs) in the CNS of adults. Multiple injury-related signals can induce OPC expansion followed by OL differentiation, axonal contact and myelin regeneration (remyelination). Therefore, OL dysfunction and regeneration failure in the deep WM of the brain are the key pathophysiological mechanisms leading to delayed brain injury after CO poisoning. CO-induced toxicity may interfere with OL function and render OPCs unable to regenerate OLs through some unclear mechanisms, leading to progressive demyelinating damage and resulting in DNS. In the future, combination therapies to reduce OL damage and promote OPC differentiation and remyelination may be important for the prevention and treatment of DNS after CO poisoning. Background Carbon monoxide (CO) poisoning is one of the most common types of poisonings in the world with high mortality, and survivors are prone to develop varying degrees of brain damage [1] . Approximately 30% of patients surviving acute CO poisoning may show delayed neurological sequelae (DNS; also called delayed encephalopathy), which refers to the recurrence of neuropsychiatric symptoms after an interval of apparent normality following apparent recovery from acute poisoning symptoms. DNS is also called ‘lucid interval’ (2–60 days, with mean duration of 22 days). The characteristic neuropsychiatric symptoms include psychiatric symptoms, unresponsiveness, low intelligence, dementia, increased muscle tension in the extremities, incontinence and coma. The clinical outcomes vary widely from complete recovery to progressive deterioration until the end of a vegetative state or death, resulting in serious economic and social burden [2] , [3] , [4] .