The role of Na⁺‐K⁺‐ATPasein the epileptic brain

Abstract

It is essential for normal structure and function of all cell membranes. Itsprimaryfunctionsincludemaintenanceiongradientacrossmembranes 2-4 anduptakeandreleaseofneurotransmitters. 5-7 Therefore, Na+-K+-ATPaseplaysacrucialroleinionhomeostasisandcellular excitability. Dysfunction of Na+-K+-ATPasemayleadtomanytypes ofcentralnervoussystem(CNS)disorders,includingepilepsy. 8-11 Epilepsyisacommonneurologicaldisordercharacterizedbyrecurrentspontaneousseizures, 12 causedbythehighlysynchronized firingofneuronswithhyperexcitability. 13 It affects about 70 million population around the world. 14 Unfortunately, about one-third of epilepticpatientsremaindrug-resistant, 15 leadingtoasituationthat needsamoreeffectivedrugtarget.Anincreasingnumberofstudies unveiled a significant role of Na+-K+-ATPase in epilepsy. Notably, mutation of genes encoding Na+-K+-ATPase leads to epilepsy as partofitsphenotype.Inrodentmodelsofepilepsy,theactivityof Na+-K+-ATPasewasreportedtochangeaswell.Pharmacologicalinhibition of Na+-K+-ATPasewillcauseepilepticseizureinrodentsas well. Na+-K+-ATPaseactivatingantibody,bycontrast,wasreported tohaveaprotectiveeffectonepilepsy.However,discordantresults arenotuncommon,probablyduetodifferencesinetiologies,testing timing, features of various epilepsy models, etc. Hence, in this review,webrieflysummarizestructureandphysiologicalfunctionof Na+-K+-ATPaseintheCNS.Thenweaimtosummarizeandevaluate currentunderstandingsofNa+-K+-ATPaseandepilepsy,hopingto provideacomprehensiveandnovelviewontheroleofATPaseinthe epileptic brain and also therapeutic strategies associated with the

Circadian Rhythms of the Blood-Brain Barrier and Drug Delivery

“…Adequate levels of these ions are required for energy-dependent processes, such as ATP synthesis, which are essential for maintaining cellular function in the brain. 127,128 Ca 2+ ions also play an important role in the regulation of BBB permeability through its modulation of TJs and adherens junctions expression. 129,130 Circadian rhythms in ions such as Ca 2+ , K + , and Na + are also controlled by the molecular clock.…”

Neuroimmunology of rabies: New insights into an ancient disease

“…115 Thus, increased expression of those transporters may be linked with neuronal dysfunction. 116,117 Furthermore, the whole-brain proteomic analysis 114 indicated a dysregulation of calcium signaling in RABV-infected cells, which was functionally confirmed by calcium-imaging tracing studied by Kim et al 10 These researchers showed that RABV differentially downregulates a range of genes related to cellular and synaptic functions by activating Ras/Erk/MAPK signaling in an M-protein-dependent manner to mediate Ca 2+ downregulation. Reduction in the calcium concentrations negatively affects neurons' spontaneous activity, which was reported during the disease kinetics.…”

EP1 receptor: Devil in emperors coat

“…54 The mechanism through which PGE2 invokes seizures is not clear but integral membrane protein Na + , K + -ATPase shows reduced activity in epilepsy. 55 In PTZadministered mice, EP1 and EP3 agonists steeply decreased the Na + , K + -ATPase activity, and EP1 and EP3 antagonists attenuated the effect of PTZ-induced decreased activity of Na + , K + -ATPase. 54 It has been found that EP1 activation during or after epilepticus causes neurodegeneration in hippocampal regions of mice and EP1-KO mice show neuroprotection against high concentrations of kainic acid.…”

“…Antagonists against these two receptors alleviated epilepsy in pentylenetetrazole (PTZ)‐induced seizures in mice and agonists against these receptors ONO‐DI‐004 and ONO‐AE‐248 induced the seizures 54 . The mechanism through which PGE2 invokes seizures is not clear but integral membrane protein Na + , K + ‐ATPase shows reduced activity in epilepsy 55 . In PTZ‐administered mice, EP1 and EP3 agonists steeply decreased the Na + , K + ‐ATPase activity, and EP1 and EP3 antagonists attenuated the effect of PTZ‐induced decreased activity of Na + , K + ‐ATPase 54 .…”