Role of calcium in sigma-mediated neuroprotection in rat primary cortical neurons.
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.
Klette
K L
KL
Division of Forensic Toxicology, Armed Forces Institute of Pathology, Washington, DC 20307-5100, USA.
DeCoster
M A
MA
Moreton
J E
JE
Tortella
F C
FC
D000818:Animals; D002118:Calcium / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects*; D018698:Glutamic Acid / Q000494:pharmacology; D008024:Ligands; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D017480:Receptors, sigma / Q000187:drug effects / Q000502:physiology*
D008024:Ligands; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; D018698:Glutamic Acid; D011189:Potassium Chloride; D002118:Calcium