title: Potent sigma 1-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine provides ischemic neuroprotection without altering dopamine accumulation in vivo in rats.
abstract: The in vivo signaling of ischemic neuroprotection provided by sigma-receptor ligands remains unclear. Catecholamines have been implicated in the propagation of ischemic neuronal injury, and previous in vitro studies suggest that sigma ligands modulate dopaminergic neurotransmission. In this study, we tested the hypothesis that the potent sigma(1)-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) attenuates the increase of extracellular dopamine in ischemic striatum. Under controlled physiological conditions, a microdialysis probe was implanted in right caudoputamen (CP) complex of adult male Wistar rats. Rats were subjected to 2 h of transient middle cerebral artery occlusion (MCAO) by the intraluminal suture technique. In a blinded, randomized fashion, rats were divided into five treatment groups: Group 1 (n = 8; saline-saline) continuous i.v. infusion of saline vehicle 30 min before MCAO followed by saline at reperfusion until the end of the experiment; Group 2 (n = 8; PPBP-PPBP) i.v. PPBP 30 min before MCAO followed by 1 micromol x kg(-1) x h(-1) of PPBP; Group 3 (n = 8; saline-PPBP) i.v. saline before MCAO followed by PPBP; Group 4 (n = 4) surgical shams (saline-saline); and Group 5 (n = 4) surgical shams (PPBP-PPBP). Infarction volume at 22 h of reperfusion in the CP complex (percentage of ipsilateral structure) was significantly attenuated in rats treated with PPBP-PPBP (27.3% +/- 9.1%) and saline-PPBP (27.8% +/- 12.7%) compared with saline-saline (59.3% +/- 7.3%) treatment. There was a three- to fourfold increase in dopamine concentrations in the microdialysates within 40 min of the onset of MCAO. Dopamine and its metabolites dihydroxy phenylacetic acid and homovallinic acid levels were similar among the three groups subjected to MCAO. Therefore, PPBP provides significant ischemic neuroprotection in the CP complex without altering the acute accumulation of dopamine in vivo during transient focal ischemia in the rat.
authors.affiliation: Department of Anesthesiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Toru
authors.initials: T
authors.lastname: Goyagi
authors.forename: Anish
authors.initials: A
authors.lastname: Bhardwaj
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Koehler
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Traystman
authors.forename: Patricia D
authors.initials: PD
authors.lastname: Hurn
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Kirsch
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001784:Blood Gas Analysis; D001831:Body Temperature / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D002545:Brain Ischemia / Q000473:pathology*; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006220:Haloperidol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D020768:Middle Cerebral Artery / Q000502:physiology; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000187:drug effects*; D015427:Reperfusion Injury / Q000378:metabolism; D000097605:Sigma-1 Receptor
chemical_list: D015102:3,4-Dihydroxyphenylacetic Acid; D004298:Dopamine; D006220:Haloperidol; D006719:Homovanillic Acid; D018696:Neuroprotective Agents; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C094850:4-phenyl-1-(4-phenylbutyl)piperidine