title: Critical role of large-conductance calcium- and voltage-activated potassium channels in leptin-induced neuroprotection of N-methyl-d-aspartate-exposed cortical neurons.
abstract: In the present study, the neuroprotective effects of the adipokine leptin, and the molecular mechanism involved, have been studied in rat and mice cortical neurons exposed to N-methyl-d-aspartate (NMDA) in vitro. In rat cortical neurons, leptin elicited neuroprotective effects against NMDA-induced cell death, which were concentration-dependent (10-100 ng/ml) and largest when the adipokine was preincubated for 2h before the neurotoxic stimulus. In both rat and mouse cortical neurons, leptin-induced neuroprotection was fully antagonized by paxilline (Pax, 0.01-1 μM) and iberiotoxin (Ibtx, 1-100 nM), with EC50s of 38 ± 10 nM and 5 ± 2 nM for Pax and Ibtx, respectively, close to those reported for Pax- and Ibtx-induced Ca(2+)- and voltage-activated K(+) channels (Slo1 BK channels) blockade; the BK channel opener NS1619 (1-30 μM) induced a concentration-dependent protection against NMDA-induced excitotoxicity. Moreover, cortical neurons from mice lacking one or both alleles coding for Slo1 BK channel pore-forming subunits were insensitive to leptin-induced neuroprotection. Finally, leptin exposure dose-dependently (10-100 ng/ml) increased intracellular Ca(2+) levels in rat cortical neurons. In conclusion, our results suggest that Slo1 BK channel activation following increases in intracellular Ca(2+) levels is a critical step for leptin-induced neuroprotection in NMDA-exposed cortical neurons in vitro, thus highlighting leptin-based intervention via BK channel activation as a potential strategy to counteract neurodegenerative diseases.
authors: Department of Medicine and Health Science, University of Molise, Campobasso, Italy; Department of Science and Technology, University of Sannio, Benevento, Italy; Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University and Jena University Hospital, Jena, Germany.
authors: Maria
authors: M
authors: Mancini
authors: Department of Medicine and Health Science, University of Molise, Campobasso, Italy.
authors: Maria Virginia
authors: MV
authors: Soldovieri
authors: Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University and Jena University Hospital, Jena, Germany.
authors: Guido
authors: G
authors: Gessner
authors: Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.
authors: Bianka
authors: B
authors: Wissuwa
authors: Department of Neuroscience, University of Naples "Federico II", Naples, Italy.
authors: Vincenzo
authors: V
authors: Barrese
authors: Department of Neuroscience, University of Naples "Federico II", Naples, Italy.
authors: Francesca
authors: F
authors: Boscia
authors: Department of Neuroscience, University of Naples "Federico II", Naples, Italy.
authors: Agnese
authors: A
authors: Secondo
authors: Department of Neuroscience, University of Naples "Federico II", Naples, Italy.
authors: Francesco
authors: F
authors: Miceli
authors: Department of Neuroscience, University of Naples "Federico II", Naples, Italy.
authors: Cristina
authors: C
authors: Franco
authors: Department of Medicine and Health Science, University of Molise, Campobasso, Italy.
authors: Paolo
authors: P
authors: Ambrosino
authors: Department of Science and Technology, University of Sannio, Benevento, Italy.
authors: Lorella Maria Teresa
authors: LM
authors: Canzoniero
authors: Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.
authors: Michael
authors: M
authors: Bauer
authors: Department of Physiology, University of Pennsylvania, Philadelphia, USA.
authors: Toshinori
authors: T
authors: Hoshi
authors: Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University and Jena University Hospital, Jena, Germany.
authors: Stefan H
authors: SH
authors: Heinemann
authors: Department of Medicine and Health Science, University of Molise, Campobasso, Italy; Department of Neuroscience, University of Naples "Federico II", Naples, Italy. Electronic address: m.taglialatela@unimol.it.
authors: Maurizio
authors: M
authors: Taglialatela
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004622:Embryo, Mammalian; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology*; D008822:Mice, Transgenic; D016202:N-Methylaspartate; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017208:Rats, Wistar
chemical_list: D051036:Large-Conductance Calcium-Activated Potassium Channels; D020738:Leptin; D018696:Neuroprotective Agents; D016202:N-Methylaspartate; D002118:Calcium
keywords: Calcium- and voltage-activated potassium channels (BK channels); Cortical neurons; Iberiotoxin; Intracellular Ca(2+) concentration; Leptin; N-methyl-d-aspartate (NMDA); Neuroprotection; Paxilline