Neuroprotective sigma ligands attenuate NMDA and trans-ACPD-induced calcium signaling in rat primary neurons

Brain Research
K L KletteF C Tortella

Abstract

The effect of neuroprotective sigma ligands possessing a range of relative selectivity for sigma and phencyclidine (PCP) binding sites on N-methyl-D-aspartate (NMDA) and (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD)-stimulated calcium flux was studied in 12-15-day-old primary cultures of rat cortical neurons. In approximately 80% of the neurons tested, NMDA (80 microM) caused a sustained increase in intracellular calcium ([Ca2+]i). With the exception of R-(+)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride ((+)-3-PPP) (previously shown not to be neuroprotective) all of the sigma ligands studied significantly altered NMDA-induced calcium dynamics. The primary effect of dextromethorphan, (+)-pentazocine, (+)-cyclazocine, (+)-SKF10047, carbetapentane, 1,3-di(2-tolyl) guanidine (DTG), and haloperidol was to shift the NMDA response from a sustained, to either a biphasic or a transient, calcium event. In contrast to NMDA, the primary response observed in 62% of the neurons treated with trans-ACPD (100 microM) was a transient elevation in [Ca2+]i. Here, however, only the highly selective neuroprotective sigma ligands (i.e., those lacking substantial PCP binding affinity) significantly decreased the number of ...Continue Reading

Citations

Mar 22, 2002·The Journal of Pharmacology and Experimental Therapeutics·Alicia E DerbezLinda L Werling
Sep 22, 2006·The Journal of Pharmacology and Experimental Therapeutics·Christopher KatnikJavier Cuevas
Mar 14, 2002·Journal of Neuroscience Research·Mark A DeCosterNicolas G Bazan
Apr 12, 2007·Headache·Nabih M Ramadan
Apr 20, 2004·The European Journal of Neuroscience·Magali PeetersEmmanuel Hermans
Aug 8, 2019·Trends in Pharmacological Sciences·Hayden R Schmidt, Andrew C Kruse
Jan 28, 2021·Genes·Ilaria Pontisso, Laurent Combettes
May 1, 2021·International Journal of Molecular Sciences·Vladimir ZhemkovIlya Bezprozvanny
Nov 18, 2000·European Journal of Pharmacology·W Hong, L L Werling

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