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 2 hours 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), two blockers of Ca2+- and voltage-activated K+ channels (Slo1 BK channels), with EC50s (38±10 nM and 5±2 nM for Pax and Ibtx, respectively) close to those reported for Pax- and Ibtx-induced BK channel 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 Ca2+ levels in rat cortical neurons. In conclusion, our results suggest that Slo1 BK channel activation following increases in intracellular Ca2+ 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.

Neuroprotective actions of progesterone in an in vivo model of retinitis pigmentosa

“…As we have just reported, progesterone and some other hormones, such as leptin and 3,5,3'-triiodothyronine has been shown to have neuroprotective effects in several experimental acute brain injury models [15,45,46] Herein, we have showed that oral administration of 100 mg/kg body/weight of progesterone every 2 days, starting at PN7, significantly preserves photoreceptor cell number and decrease cell death in experimental RP model, rd1 mouse (Figures 1 and 2). While this treatment does not appear to inhibit the pathological course of the disease, it seems to slow down its progression.…”

Mexico City normal weight children exposed to high concentrations of ambient PM2.5 show high blood leptin and endothelin-1, vitamin D deficiency, and food reward hormone dysregulation versus low pollution controls. Relevance for obesity and Alzheimer disease

“…For example, do we have a central leptin resistance in urban children before weight changes take place? If so, since leptin plays a key role in the developing brain (Steppan and Swick, 1999;Stieg et al, 2015;Farr et al, 2014;Bouret, 2010;Johnston et al, 2014;Pérez-González et al, 2011;Busch et al, 2011;Folch et al, 2012;Zhang et al, 2013;Mancini et al, 2014;Davis et al, 2014) are the high leptin concentrations in serum associated with high CSF leptin and low leptin receptors mRNA in target areas like hippocampus as in Alzheimer's patients? (Bonda et al, 2014a(Bonda et al, , 2014b.…”

Leptin attenuates cerebral ischemic injury in rats by modulating the mitochondrial electron transport chain via the mitochondrial STAT3 pathway

“…Acute ischemic cerebrovascular disease is the most common cerebrovascular disease and is a common cause of death and disability. According to several recent studies (Davis, Mudd, & Hawkins, ; Mancini et al, ; Valerio et al, ), leptin represents a potential therapy for ischemic cerebrovascular disease, providing another possibility for treating stroke.…”