Role of calcium in sigma-mediated neuroprotection in rat primary cortical neurons.
Brain Res
; 704(1): 31-41, 1995 Dec 15.
Article
em En
| MEDLINE
| ID: mdl-8750959
ABSTRACT
Since unique calcium dynamics have been reported for toxic (40-80 M) and non-toxic (5-10 microM) concentrations of glutamate, we evaluated the effect of neuroprotective sigma ligands on glutamate and potassium chloride (KCl)-stimulated changes in [Ca2+]i using 12-15 day old primary rat neuronal cortical cultures. In approximately 80% of the neurons tested, 80 microM glutamate caused a sustained calcium flux previously shown to be associated with neurotoxicity. The majority of sigma ligands that were evaluated altered glutamate-induced calcium flux. For example, the primary effect of maximally neuroprotective concentrations of the sigma ligands dextromethorphan, (+)-pentazocine, (+)-cyclazocine, (+)-SKF 10047, carbetapentane and haloperidol was a shift from a sustained, to either a biphasic or a monophasic transient calcium response indicative of neuroprotection. (+)-3-PPP, previously shown not to be neuroprotective in this model system, failed to alter glutamate-induced calcium flux. In contrast to glutamate, KCl (50 mM) produced changes in [Ca2+]i which were not neurotoxic to the neurons as measured by LDH release. The primary response observed in 59% of the neurons treated with 50 mM KCl alone was an initial spike in [Ca2+]i which abruptly declined then plateaued above basal levels throughout the 12 min of analysis (modified sustained response). The highly selective sigma ligands produced a shift from the modified sustained response to a monophasic transient calcium response. Again, (+)-3-PPP had no effect on KCl-induced calcium dynamics. Of the PCP-related sigma ligands only (+)-SKF-10047 consistently attenuated the KCl-induced calcium flux. Collectively, these results indicate that modulation of [Ca2+]i through receptor and voltage-gated calcium channels contributes significantly to sigma mediated neuroprotection.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Córtex Cerebral
/
Cálcio
/
Receptores sigma
/
Receptores de N-Metil-D-Aspartato
/
Fármacos Neuroprotetores
/
Neurônios
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Brain Res
Ano de publicação:
1995
Tipo de documento:
Article
País de afiliação:
Estados Unidos