A novel mechanism for the anticonvulsant effect of furosemide in rat hippocampus in vitro

作者：Uwera Josiane; Nedergaard Steen; Andreasen Mogens^*

来源：Brain Research, 2015, 1625: 1-8.

DOI：10.1016/j.brainres.2015.08.014

• Furosemide
• NKCC1
• KCC2
• Cl-/HCO3--exchanger
• Seizure
• pH(i)

Though both in vivo and in vitro studies have demonstrated an anticonvulsant effect of the loop diuretic furosemide, the precise mechanism behind this effect is still debated. The current study investigates the effect of furosemide on Cs-induced epileptiform activity (Cs-FP) evoked in area CA1 of rat hippocampal slices in the presence of Cs+ (5 mM) and ionotropic glutamatergic and GABAergic receptor antagonists. As this model diverges in several respects from other epilepsy models it can offer new insight into the mechanism behind the anticonvulsive effect of furosemide. The present study shows that furosemide suppresses the Cs-FP in a dose-dependent manner with a near complete block at concentrations >= 1.25 mM. Because furosemide targets several types of ion transporters we examined the effect of more selective antagonists. Bumetanide (2011 mu M), which selectively inhibits the Na-K-2Cl co-transporter (NKCC1), had no significant effect on the Cs-FP. VU0240551 (10 mu M), a selective antagonist of the K-Cl co-transporter (KCC2), reduced the ictal-like phase by 51.73 +/- 8.5% without affecting the interictal-like phase of the Cs-FP. DIDS (50 mu M), a nonselective antagonist of Cl-/HCO3--exchangers, Na+-HCO3- cotransporters, chloride channels and KCC2, suppressed the ictal-like phase by 60.8 +/- 8.1% without affecting the interictal-like phase. At 500 44, DIDS completely suppressed the Cs-FP. Based on these results we propose that the anticonvulsant action of furosemide in the Cs+-model is exerted through blockade of the neuronal KCC2 and Na+-independent Cl-/HCO3--exchanger (AE3) leading to stabilization of the activity-induced intracellular acidification in CA1 pyramidal neurons.

• 出版日期2015-11-2