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: Maria Mancini, Maria Virginia Soldovieri, Guido Gessner, Bianka Wissuwa, Vincenzo Barrese, Francesca Boscia, Agnese Secondo, Francesco Miceli, Cristina Franco, Paolo Ambrosino, Lorella Maria Teresa Canzoniero, Michael Bauer, Toshinori Hoshi, Stefan H Heinemann, Maurizio Taglialatela
• Journal: Pharmacological research (Pharmacol Res) Vol. 87 Pg. 80-6 (Sep 2014) ISSN: 1096-1186 [Electronic] Netherlands
• PMID: 24973659 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Large-Conductance Calcium-Activated Potassium Channels
• Leptin
• Neuroprotective Agents
• N-Methylaspartate
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Cells, Cultured
• Cerebral Cortex (cytology)
• Embryo, Mammalian
• Large-Conductance Calcium-Activated Potassium Channels (metabolism)
• Leptin (pharmacology)
• Mice, Transgenic
• N-Methylaspartate
• Neurons (drug effects, metabolism)
• Neuroprotective Agents (pharmacology)
• Rats, Wistar