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 (10-100ng/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, 0.01-1μM) and iberiotoxin (Ibtx, 1-100nM), with EC50s of 38±10nM and 5±2nM 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 (1-30μM) 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 (10-100ng/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
Critical role of large-conductance calcium- and voltage-activated potassium channels in leptin-induced neuroprotection of N-methyl-d-aspartate-exposed cortical neurons / Mancini, Maria; Maria Virginia Soldovieri, ; Gessner, Guido; Wissuwa, Bianka; Barrese, Vincenzo; Boscia, Francesca; Secondo, Agnese; Miceli, Francesco; Franco, Cristina; Ambrosino, Paolo; Lorella Maria Teresa Canzoniero, ; Bauer, Michael; Hoshi, Toshinori; Heinemann, Stefan H.; Taglialatela, Maurizio. - In: PHARMACOLOGICAL RESEARCH. - ISSN 1043-6618. - 87:(2014), pp. 80-86. [10.1016/j.phrs.2014.06.010]
Critical role of large-conductance calcium- and voltage-activated potassium channels in leptin-induced neuroprotection of N-methyl-d-aspartate-exposed cortical neurons
Vincenzo Barrese;BOSCIA, FRANCESCA;SECONDO, AGNESE;MICELI, Francesco;TAGLIALATELA, MAURIZIO
2014
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 (10-100ng/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, 0.01-1μM) and iberiotoxin (Ibtx, 1-100nM), with EC50s of 38±10nM and 5±2nM 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 (1-30μM) 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 (10-100ng/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 diseasesFile | Dimensione | Formato | |
---|---|---|---|
Pharm Res 2014 Leptin and BK.pdf
accesso aperto
Tipologia:
Documento in Post-print
Licenza:
Dominio pubblico
Dimensione
1.33 MB
Formato
Adobe PDF
|
1.33 MB | Adobe PDF | Visualizza/Apri |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.