Potent sigma 1-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine provides ischemic neuroprotection without altering dopamine accumulation in vivo in rats.

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.

[1]  J. Weinberger,et al.  Ischemia in the dorsal hippocampus is associated with acute extracellular release of dopamine and norepinephrine , 1990, Journal of Neural Transmission / General Section JNT.

[2]  J. Weinberger,et al.  Pentobarbital inhibits extracellular release of dopamine in the ischemic striatum , 1990, Journal of Neural Transmission / General Section JNT.

[3]  J. Weinberger,et al.  Monoamine neurotransmitters in the evolution of infarction in ischemic striatum: morphologic correlation , 2005, Journal of Neural Transmission.

[4]  J. Weinberger,et al.  Metabolism of monoamine neurotransmitters in the evolution of infarction in ischemic striatum , 2005, Journal of Neural Transmission.

[5]  Coy W. Miller,et al.  Modulation of dopamine uptake in rat nucleus accumbens: effect of specific dopamine receptor antagonists and sigma ligands , 2001, Neuroscience Letters.

[6]  S. Takahashi,et al.  MS-377, a novel selective sigma(1) receptor ligand, reverses phencyclidine-induced release of dopamine and serotonin in rat brain. , 2001, European journal of pharmacology.

[7]  V. Dawson,et al.  Neuroprotective effect of σ1-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) is linked to reduced neuronal nitric oxide production , 2001 .

[8]  R. Traystman,et al.  sigma(1)-receptor ligand 4-phenyl-1-(4-phenylbutyl)-piperidine affords neuroprotection from focal ischemia with prolonged reperfusion. , 2000, Stroke.

[9]  I. Acworth,et al.  The Measurement of Monoamine Neurotransmitters in Microdialysis Perfusates Using HPLC-ECD. , 1999, Methods in molecular medicine.

[10]  G. Gudelsky.  Biphasic effect of sigma receptor ligands on the extracellular concentration of dopamine in the striatum of the rat , 1999, Journal of Neural Transmission.

[11]  R. Traystman,et al.  Neuroprotection from Focal Ischemia by 4-Phenyl-1-(4-Phenylbutyl) Piperidine (PPBP) Is Dependent on Treatment Duration in Rats , 1998, Anesthesia and analgesia.

[12]  R. Koehler,et al.  Potent sigma1-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine modulates basal and N-methyl-D-aspartate-evoked nitric oxide production in vivo. , 1998, Stroke.

[13]  S. Chaki,et al.  Regulation of NMDA-induced [3H] dopamine release from rat hippocampal slices through sigma-1 binding sites , 1998, Neurochemistry International.

[14]  R. Traystman,et al.  Postischemic Brain Injury Is Affected Stereospecifically by Pentazocine in Rats , 1997, Anesthesia and analgesia.

[15]  R. Koehler,et al.  PPBP [4-phenyl-1-(4-phenylbutyl) piperidine] decreases brain injury after transient focal ischemia in rats. , 1996, Stroke.

[16]  F. Tortella,et al.  Role of calcium in sigma-mediated neuroprotection in rat primary cortical neurons , 1995, Brain Research.

[17]  R. Koehler,et al.  PPBP [4-phenyl-1-(4-phenylbutyl) piperidine], a potent sigma-receptor ligand, decreases brain injury after transient focal ischemia in cats. , 1995, Stroke.

[18]  D. Hanley,et al.  Adenosine modulates N-methyl-D-aspartate-stimulated hippocampal nitric oxide production in vivo. , 1995, Stroke.

[19]  J. Leysen,et al.  Neuroprotective sigma ligands interfere with the glutamate‐activated NOS pathway in hippocampal cell culture , 1995, Synapse.

[20]  D. Reich,et al.  Nitric Oxide Modulates Dopamine Release During Global Temporary Cerebral Ischemia , 1995, Anesthesia and analgesia.

[21]  E. London,et al.  In vivo labeling of sigma receptors in mouse brain with [3H]4‐phenyl‐1‐(4‐phenylbutyl)piperidine , 1995, Synapse.

[22]  P. Soulard,et al.  Distinct neuroprotective profiles for σ ligands against N-methyl-d-aspartate (NMDA), and hypoxia-mediated neurotoxicity in neuronal culture toxicity studies , 1995, Brain Research.

[23]  J. Clemens,et al.  Ischemia increases tissue and decreases extracellular levels of acid dopamine metabolites in the rat striatum: further evidence for active transport of metabolites. , 1995, Life sciences.

[24]  F. Tortella,et al.  σ receptor-mediated neuroprotection against glutamate toxicity in primary rat neuronal cultures , 1995, Brain Research.

[25]  T. Yamamoto,et al.  Sigma ligands indirectly modulate the NMDA receptor-ion channel complex on intact neuronal cells via sigma 1 site , 1995, Journal of Neuroscience.

[26]  L. Werling,et al.  Regulation of [3H]dopamine release from rat striatal slices by sigma receptor ligands. , 1994, The Journal of pharmacology and experimental therapeutics.

[27]  R. Willette,et al.  A comparison of (+) SK & F 10047 and MK-801 on cortical spreading depression , 1994, Brain Research.

[28]  D. Reich,et al.  Effect of etomidate on in vivo ischemia-induced dopamine release in the corpus striatum of the rat: a study using cerebral microdialysis. , 1994, Anesthesia and analgesia.

[29]  M. Delivoria-Papadopoulos,et al.  Levels of dopamine and its metabolites in the extracellular medium of the striatum of newborn piglets during graded hypoxia. , 1994, Advances in experimental medicine and biology.

[30]  D. Reich,et al.  Effect of Isoflurane and Halothane on In Vivo Ischemia‐induced Dopamine Release in the Corpus Striatum of the Rat A Study Using Cerebral Microdialysis , 1993, Anesthesiology.

[31]  K. Matsuno,et al.  Increase in extracellular acetylcholine level by sigma ligands in rat frontal cortex. , 1993, The Journal of pharmacology and experimental therapeutics.

[32]  A. Ceci,et al.  Non-competitive N-methyl-d-aspartate antagonists are potent activators of ventral tegmental A10 dopamine neurons , 1990, Neuroscience Letters.

[33]  P. Lipton,et al.  σ-Ligands and non-competitive NMDA antagonists inhibit glutamate release during cerebral ischemia , 1990, Neuroscience Letters.

[34]  U. Ungerstedt,et al.  Intracerebral microdialysis: I. Experimental studies of diffusion kinetics. , 1989, Journal of pharmacological methods.

[35]  Anne W. Schmidt,et al.  Sertraline potently displaces (+)-[3H]3-PPP binding to σ sites in rat brain , 1989 .

[36]  P. Weinstein,et al.  Reversible middle cerebral artery occlusion without craniectomy in rats. , 1989, Stroke.

[37]  R. Busto,et al.  Intra-ischemic extracellular release of dopamine and glutamate is associated with striatal vulnerability to ischemia , 1988, Neuroscience Letters.

[38]  J. Weinberger,et al.  Increase in Extracellular Dopamine in the Striatum During Cerebral Ischemia: A Study Utilizing Cerebral Microdialysis , 1988, Journal of neurochemistry.

[39]  R. Busto,et al.  Substantia nigra lesion protects against ischemic damage in the striatum , 1987, Neuroscience Letters.

[40]  J. Weinberger,et al.  Direct Evidence of Acute, Massive Striatal Dopamine Release in Gerbils with Unilateral Strokes , 1987, Stroke.

[41]  H. Maker,et al.  Amine-mediated toxicity The effects of dopamine, norepinephrine, 5-hydroxytryptamine, 6-hydroxydopamine, ascorbate, glutathione and peroxide on the in vitro activities of creatine and adenylate kinases in the brain of the rat , 1986, Neuropharmacology.

[42]  J. Weinberger,et al.  Nerve terminal damage in cerebral ischemia: protective effect of alpha-methyl-para-tyrosine. , 1985, Stroke.

[43]  F. Fonnum.  Glutamate: A Neurotransmitter in Mammalian Brain , 1984, Journal of neurochemistry.

[44]  J. Weinberger,et al.  Nerve terminal damage in cerebral ischemia: greater susceptibility of catecholamine nerve terminals relative to serotonin nerve terminals. , 1983, Stroke.

[45]  J. B. Justice,et al.  Model studies for brain dialysis , 1983, Brain Research Bulletin.