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Received for publication May 10, 2006.
Revised September 11, 2006.
Accepted for publication September 12, 2006.
Sigma receptors are putative targets for neuroprotection following ischemia; however, little is known on their mechanism of action. One of the key components in the demise of neurons following ischemic injury is the disruption of intracellular calcium homeostasis. Fluorometric calcium imaging was used to examine the effects of sigma receptor activation on changes in intracellular calcium concentrations ([Ca2+]i) evoked by in vitro ischemia in cultured cortical neurons from embryonic rats. The sigma receptor agonist, DTG, was shown to depress [Ca2+]i elevations observed in response to ischemia induced by sodium azide and glucose deprivation. Two sigma receptor antagonists, metaphit and BD-1047, were shown to blunt the ability of DTG to inhibit ischemia-evoked increases in [Ca2+]i, revealing that the effects are mediated by activation of sigma receptors and not via the actions of DTG on non-specific targets such as NMDA receptors. DTG inhibition of ischemia-induced increases in [Ca2+]i was mimicked by the sigma-1 receptor-selective agonists, carbetapentane, (+)-pentazocine and PRE-084, but not by the sigma-2 selective agonist, ibogaine, showing that activation of sigma-1 receptors is responsible for the effects. In contrast, DTG, carbetapentane and ibogaine blocked spontaneous, synchronous calcium transients observed in our preparation at concentrations consistent with sigma receptor mediated effects, indicating that both sigma-1 and sigma-2 receptors regulate events that affect [Ca2+]i in cortical neurons. Our studies show that activation of sigma receptors can ameliorate [Ca2+]i dysregulation associated with ischemia in cortical neurons, and thus identify one of the mechanisms by which these receptors may exert their neuroprotective properties.
Key words:
excitotoxicity, intracellular calcium, ischemia, neuroprotection, sigma receptors, stroke
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