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Neuroprotective sigma ligands attenuate NMDA and trans-ACPD-induced calcium signaling in rat primary neurons
- Source :
- Brain Research. 756:231-240
- Publication Year :
- 1997
- Publisher :
- Elsevier BV, 1997.
-
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 transient responses elicited by trans-ACPD whereas the PCP-related sigma ligands such as dextromethorphan, (+)-SKF10047 and (+)-cyclazocine were ineffective. Unexpectedly, (+)-3-PPP potentiated trans-ACPD activity. These results demonstrating attenuating effects of sigma ligands on NMDA-stimulated neuronal calcium responses agree with earlier studies using glutamate and KCl and identify a sigma receptor modulation of functional NMDA responsiveness. Furthermore, the ability of sigma ligands to attenuate NMDA-, trans-ACPD- and KCl-evoked neuronal calcium dynamics indicates that the receptor mechanisms mediating sigma neuroprotection comprise complex interactions involving ionotropic, metabotropic, and even voltage-gated calcium signaling processes.
- Subjects :
- N-Methylaspartate
Sigma receptor
chemistry.chemical_element
Calcium
Ligands
Neuroprotection
Calcium in biology
Rats, Sprague-Dawley
Calcium flux
medicine
Animals
Receptors, sigma
Cycloleucine
Molecular Biology
Phencyclidine
Cells, Cultured
Neurons
General Neuroscience
Rats
Neuroprotective Agents
Metabotropic receptor
chemistry
Biochemistry
Biophysics
NMDA receptor
Neurology (clinical)
Signal Transduction
Developmental Biology
medicine.drug
Subjects
Details
- ISSN :
- 00068993
- Volume :
- 756
- Database :
- OpenAIRE
- Journal :
- Brain Research
- Accession number :
- edsair.doi.dedup.....8ac9b364d72a4790064bdb7598f13104