title: Sigma 1 receptor agonists act as neuroprotective drugs through inhibition of inducible nitric oxide synthase.
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/Bl6 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.
authors.affiliation: Department of Anesthesiology and Peri-Operative Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road UHS-2, Portland, Oregon 97239, USA.
authors.forename: Kamila
authors.initials: K
authors.lastname: Vagnerova
authors.forename: Patricia D
authors.initials: PD
authors.lastname: Hurn
authors.forename: Anish
authors.initials: A
authors.lastname: Bhardwaj
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Kirsch
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D010423:Pentazocine / Q000494:pharmacology; D017480:Receptors, sigma / Q000819:agonists*; D000097605:Sigma-1 Receptor
chemical_list: D002118:Calcium; D004791:Enzyme Inhibitors; D006146:Guanidines; D018696:Neuroprotective Agents; D052247:Nitric Oxide Synthase Type II; D010423:Pentazocine; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C004479:pimagedine