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

Research output: Contribution to journalArticle

41 Citations (Scopus)

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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Neuroprotective Agents
Nitric Oxide Synthase Type II
Placebos
Brain Injuries
Protein Isoforms
Cell Death
Pentazocine
Middle Cerebral Artery Infarction
Neocortex
Therapeutics
sigma-1 receptor
pimagedine
Infarction
Reperfusion
Histology
Pharmaceutical Preparations
Neuroprotection

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Sigma 1 receptor agonist act as neuroprotective drugs through inhibition of inducible nitric oxide synthase. / Vagnerova, Kamila; Hurn, Patricia D.; Bhardwaj, Anish; Kirsch, Jeffrey R.

In: Anesthesia and Analgesia, Vol. 103, No. 2, 08.2006, p. 430-434.

Research output: Contribution to journalArticle

Vagnerova, Kamila ; Hurn, Patricia D. ; Bhardwaj, Anish ; Kirsch, Jeffrey R. / Sigma 1 receptor agonist act as neuroprotective drugs through inhibition of inducible nitric oxide synthase. In: Anesthesia and Analgesia. 2006 ; Vol. 103, No. 2. pp. 430-434.
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