Abstract
In adults, γ-aminobutyric acid (GABA) type A receptor (GABAAR)-mediated inhibition depends on the maintenance of low intracellular chloride anion concentration through neuron-specific potassium-chloride cotransporter-2 (KCC2). KCC2 has been widely reported to have a plasticity change during the course of epilepsy development, with an early downregulation and late recovery in neuronal cell membranes after epileptic stimulation, which facilitates epileptiform burst activity. Furosemide is a clinical loop diuretic that inhibits KCC2. Here, we first confirmed that furosemide pretreatment could effectively prevented convulsant stimulation-induced neuronal membrane KCC2 downregulation in the hippocampus in both in vivo and in vitro cyclothiazide-induced seizure model. Second, we verified that furosemide pretreatment rescued KCC2 function deficits, as indicated by E GABA depolarizing shift and GABAAR inhibitory function impairment induced via cyclothiazide treatment. Further, we demonstrated that furosemide also suppressed cyclothiazide-induced epileptiform burst activity in cultured hippocampal neurons and lowered the mortality rate during acute seizure induction. Overall, furosemide prevents membrane KCC2 downregulation during acute seizure induction, restores KCC2-mediated GABA inhibition, and interrupts the progression from acute seizure to epileptogenesis.