Abstract
Oligodendrocyteswrap multiple lamellae of their membrane,myelin, around axons of the central nervoussystem(CNS), to improve impulse conduction.Myelinsynthesisis specialisedand dynamic,responsive to local neuronal excitation.Subtlepathological insultsaresufficienttocausesignificant neuronalmetabolicimpairment, somyelinpreservationis necessary to safeguard neural networks.Multiple sclerosis (MS) is the mostprevalentdemyelinating disease of theCNS. In MS,inflammatoryattacksagainst myelin, proposedto beautoimmune,causemyelin decay and oligodendrocyte loss, leaving neurons vulnerable.Current therapies target theprominentneuroinflammationbut are mostly ineffective in protecting from neurodegenerationand theprogressiveneurological disability.People with MShave substantially higher levels ofextracellularglutamate, the main excitatory neurotransmitter.Thisimpairs cellular homeostasis to causeexcitotoxic stress. Large conductance Ca2 +-activated K +channels (BK channels)could preservemyelinor allowitsrecoveryby protecting cells from the resulting excessive excitability.This review evaluatesthe role ofexcitotoxic stress, myelination and BK channels in MSpathology,and explores the hypothesis thatBKchannelactivationcould be atherapeuticstrategyto protect oligodendrocytes from excitotoxic stress in MS. This couldreduce progression of neurological disabilityif used in parallel to immunomodulatory therapies.
Highlights
Oligodendrocytes wrap multiple lamellae of their membrane, myelin, around axons of the central nervous system (CNS), to improve impulse conduction
Oligodendrocytes perivascular location, as part of white matter, further increases this susceptibility, especially in Multiple sclerosis (MS) where neuroinflammatory oxidative stress is central to demyelination
It is plausible that big conductance Ca2+ activated K+ CD (BK) channels could protect oligodendrocytes from excitotoxicity, supported by their expression in these cells[118]
Summary
There are numerous ways excessive glutamate may cause oligodendrocytes toxicity in demyelinating pathology. It is important to determine whether BK channels are expressed by oligodendrocytes, whether this expression depends on developmental stage, and effects of glutamate-induced excitotoxicity in the context of myelination and the ability to target BK channels in vivo. This would define whether increasing the open conformation of BK channels with activating agents is a promising neuroprotective therapy to be used in parallel to immunosuppressive agents for the treatment of MS. Data availability Underlying data No data are associated with this article
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