This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lysko, P. G. Articles by Feuerstein, G. Search for Related Content PubMed PubMed Citation Articles by Lysko, P. G. Articles by Feuerstein, G.

Stroke, Vol 23, 414-419, Copyright © 1992 by American Heart Association

ARTICLES

Neuroprotective effects of SKF 10,047 in cultured rat cerebellar neurons and in gerbil global brain ischemia

PG Lysko, RC Gagnon, TL Yue, JL Gu and G Feuerstein
Department of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.

BACKGROUND AND PURPOSE: 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.

This article has been cited by other articles:

				A. Pal, U. B. Chu, S. Ramachandran, D. Grawoig, L.-W. Guo, A. R. Hajipour, and A. E. Ruoho Juxtaposition of the Steroid Binding Domain-like I and II Regions Constitutes a Ligand Binding Site in the {sigma}-1 Receptor J. Biol. Chem., July 11, 2008; 283(28): 19646 - 19656. [Abstract] [Full Text] [PDF]

				A. Pal, A. R. Hajipour, D. Fontanilla, S. Ramachandran, U. B. Chu, T. Mavlyutov, and A. E. Ruoho Identification of Regions of the {sigma}-1 Receptor Ligand Binding Site Using a Novel Photoprobe Mol. Pharmacol., October 1, 2007; 72(4): 921 - 933. [Abstract] [Full Text] [PDF]

				H. Takahashi, J. R. Kirsch, K. Hashimoto, E. D. London, R. C. Koehler, R. J. Traystman, and P. G. Lysko PPBP [4-Phenyl-1-(4-phenylbutyl) Piperidine] Decreases Brain Injury After Transient Focal Ischemia in Rats Stroke, November 1, 1996; 27(11): 2120 - 2123. [Abstract] [Full Text]

				H. Takahashi, J. R. Kirsch, K. Hashimoto, E. D. London, R. C. Koehler, and R. J. Traystman PPBP [4-Phenyl-1-(4-phenylbutyl) Piperidine], a Potent {varsigma}-Receptor Ligand, Decreases Brain Injury After Transient Focal Ischemia in Cats Stroke, September 1, 1995; 26(9): 1676 - 1682. [Abstract] [Full Text]

				V. S. Miller Topical Review Article: Pharmacologic Management of Neonatal Cerebral Ischemia and Hemorrhage: Old and New Directions J Child Neurol, January 1, 1993; 8(1): 7 - 18. [Abstract] [PDF]