Maddalena Rupnik, David Baker, David L Selwood
Oligodendrocytes, BK channels and the preservation of myelin
Oligodendrocytes wrap multiple lamellae of their membrane, myelin, around axons of the central nervous system (CNS), to improve impulse conduction. Myelin synthesis is specialised and dynamic, responsive to local neuronal excitation. Subtle pathological insults are sufficient to cause significant neuronal metabolic impairment, so myelin preservation is necessary to safeguard neural networks. Multiple sclerosis (MS) is the most prevalent demyelinating disease of the CNS. In MS, inflammatory attacks against myelin, proposed to be autoimmune, cause myelin decay and oligodendrocyte loss, leaving neurons vulnerable. Current therapies target the prominent neuroinflammation but are mostly ineffective in protecting from neurodegeneration and the progressive neurological disability. People with MS have substantially higher levels of extracellular glutamate, the main excitatory neurotransmitter. This impairs cellular homeostasis to cause excitotoxic stress. Large conductance Ca2+-activated K+ channels (BK channels) could preserve myelin or allow its recovery by protecting cells from the resulting excessive excitability. This review evaluates the role of excitotoxic stress, myelination and BK channels in MS pathology, and explores the hypothesis that BK channel activation could be a therapeutic strategy to protect oligodendrocytes from excitotoxic stress in MS. This could reduce progression of neurological disability if used in parallel to immunomodulatory therapies.
BK channels are big conductance calcium (Ca) activated potassium (K) channels and can deliver a neuroprotective signal to save nerves from excitotoxicity (Too much glutamate signalling causes nerves and oligodendrocyte precursors to die. We know this because there is a history of animal studies in brain/spinal cord injury and stroke and EAE studies (which we must publish). During nerve hyperstimulation leading to sodium (Na+) and calcium (Ca2+) ion entry into cells occurs. BK potassium channels open and allow potassium ions (K+) out of the cells stopping it from being excitable, this can potentially stop symptoms due to to much stimulation.
Because the channel is closed until things are going extreme, drugs that keep the channel open are very well tolerated and are virutally without side-effects. Yes unheard of. However, the drugs we made were not good enough in humans as they didn’t penetrate the brain as much as we want and they did not last very long in the circulation. We have gone back to the drawing board and you may hear about the results in due course.
COI: We filed patents in this area.