Retigabine and flupirtine exert neuroprotective actions in organotypic hippocampal cultures.
Retigabine and flupirtine are two structurally related molecules provided of anticonvulsant and analgesic actions. The present study has investigated the neuroprotective potential, as well as the possible underlying molecular mechanisms, exerted by retigabine and flupirtine in rat organotypic hippocampal slice cultures (OHSCs) exposed to N-methyl-D-aspartate (NMDA), oxygen and glucose deprivation followed by reoxygenation (OGD), or serum withdrawal (SW). Region-specific vulnerability of hippocampal subfields occurred with each of these injury models. Specifically, CA1 was the most susceptible region to both NMDA and OGD-induced neurodegeneration, whereas selective cell death in the dentate gyrus (DG) occurred upon OHSCs exposure to SW. The NMDA antagonist MK-801 (10-30 microM), despite blocking NMDA- and OGD-induced cell death, failed to prevent SW-induced neurodegeneration. Interestingly, retigabine (0.01-10 microM) and flupirtine (0.01-10 microM) dose-dependently prevented DG neuronal death induced by SW, with IC50 s of 0.4 microM and 0.7 microM, respectively. By contrast, retigabine and flupirtine (each at 10 microM) were less effective in counteracting NMDA- or OGD-induced toxicity in the CA1 region. Both retigabine and flupirtine (0.1-10 microM) reduced SW-induced ROS production in the DG with IC50 s of approximately 1 microM. This suggested that antioxidant actions of these compounds participated in OHSC neuroprotection during SW. By contrast, activation of KCNQ K+ channels seemed not to be involved in retigabine-induced OHSCs neuroprotection during SW, since linopirdine (20 microM) and XE-991 (10 microM), two KCNQ blockers, failed to reverse retigabine-induced neuronal rescue.
Boscia
Francesca
F
Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, Naples, Italy.
Annunziato
Lucio
L
Taglialatela
Maurizio
M
D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D002219:Carbamates / Q000494:pharmacology*; D016895:Culture Media, Serum-Free; D005947:Glucose / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D051656:KCNQ Potassium Channels / Q000502:physiology; D016202:N-Methylaspartate; D009410:Nerve Degeneration / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism; D010655:Phenylenediamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors; D046509:Tissue Culture Techniques
D000631:Aminopyridines; D002219:Carbamates; D016895:Culture Media, Serum-Free; D051656:KCNQ Potassium Channels; D018696:Neuroprotective Agents; D010655:Phenylenediamines; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; C101866:ezogabine; D016202:N-Methylaspartate; D005947:Glucose; C034161:flupirtine; D010100:Oxygen