title: Neuroprotective effects of SKF 10,047 in cultured rat cerebellar neurons and in gerbil global brain ischemia.
abstract: OBJECTIVE
  Excitatory amino acids and their receptors are involved in mediating ischemic neuronal damage. The sigma-agonists are believed to interact with the N-methyl-D-aspartate receptor. Therefore, we studied the neuroprotective, hypothermic, and motor deficit effects of the sigma-agonist SKF 10,047 and the N-methyl-D-aspartate antagonist MK-801.
  
  
  METHODS
  Neuroprotective effects were compared using an in vitro ischemia model of cultured rat cerebellar granule cells and the gerbil model of global brain ischemia induced by 5 minutes of bilateral carotid artery occlusion followed by 7 days of reperfusion.
  
  
  RESULTS
  In vitro, (+)MK-801 protected against 100 microM glutamate with a 50% protective concentration of 30 nM, followed by (-)MK-801 (150 nM), cyclazocine (0.5 microM), (+)SKF 10,047 (3.3 microM), pentazocine (5 microM), and (-)SKF 10,047 (10 microM). In vivo, (+)SKF 10,047 pretreatment (60 mg/kg) or multiple postischemic treatments provided neuroprotection comparable with MK-801 pretreatment (10 mg/kg). When ischemic animals were administered the multiple dosing regimen of (+)SKF 10,047, no hypothermic effect was noted in the temporalis muscle over 4 hours' postischemia. Motor deficits monitored by a swing grid test showed that 50% recovery from (+)SKF 10,047 was 5.5 times faster than recovery from MK-801.
  
  
  CONCLUSIONS
  These results are the first to report a hypothermia-free, in vivo neuroprotective effect of (+)SKF 10,047, a prototypical drug of the sigma-agonist class.
authors.affiliation: Department of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.
authors.forename: P G
authors.initials: PG
authors.lastname: Lysko
authors.forename: R C
authors.initials: RC
authors.lastname: Gagnon
authors.forename: T L
authors.initials: TL
authors.lastname: Yue
authors.forename: J L
authors.initials: JL
authors.lastname: Gu
authors.forename: G
authors.initials: G
authors.lastname: Feuerstein
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002545:Brain Ischemia / Q000473:pathology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects* / Q000473:pathology; D003496:Cyclazocine / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005849:Gerbillinae; D010423:Pentazocine / Q000494:pharmacology; D010620:Phenazocine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D013237:Stereoisomerism
chemical_list: D016291:Dizocilpine Maleate; C012134:SK&F 10047; D010620:Phenazocine; D003496:Cyclazocine; D010423:Pentazocine