Sigma 1 receptor agonist act as neuroprotective drugs through inhibition of inducible nitric oxide synthase

Kamila Vagnerova, Patricia D. Hurn, Anish Bhardwaj, Jeffrey R. Kirsch

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Abstract

Postischemic administration of the sigma-1 agonists reduces ischemic brain injury; however, the mechanism is unclear. We hypothesized that the sigma-1 agonist (+)isoform of pentazocine (P(+)) reduces damage in part by ameliorating cell death mediated via inducible nitric oxide synthase (iNOS) and that the (-)isoform (P(-)) lacks this effect. We compared treatment with P(+) with or without the iNOS inhibitor aminoguanidine (AG) and also the effects of P(+) in iNOS deficient (iNOSKO) mice. A possible mechanism of neuroprotection is inhibition of iNOS expression. Male C57/B16 mice were subjected to transient middle cerebral artery occlusion (90 min) and drugs were administered with reperfusion: 1) P(+) with AG (P+ /AG), 2) P(+), 3) P(-), 4) AG, or 5) placebo. iNOSKOs were treated with either P(+) or placebo. Infarction (triphenyltetrazolium chloride histology, 72 h) was reduced by P(+) treatment in striatum by 44% and in neocortex by 23% versus placebo (P < 0.05), a reduction comparable to AG effect. P(-) did not attenuate brain injury. There was no difference in P(+)/AG treatment compared with showed the same level of neuroprotection as P(+) alone. P(+) also did not provide further neuroprotection for iNOSKOs. We conclude that postischemic administration of P(+) reduces infarct volume in mice. Because AG provides no additional benefit to P(+) treatment and iNOSKOs do not benefit from P(+), we speculate that P(+) acts by suppressing cell death resulting from iNOS toxicity.

Original languageEnglish (US)
Pages (from-to)430-434
Number of pages5
JournalAnesthesia and Analgesia
Volume103
Issue number2
DOIs
StatePublished - Aug 2006
Externally publishedYes

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ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

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