Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Potent sigma 1-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine provides ischemic neuroprotection without altering dopamine accumulation in vivo in rats. 1253 8

Previous studies indicate that the Sigma-1 ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) protects the brain from ischemia. Less clear is whether protection is mediated by agonism or antagonism of the Sigma-1 receptor, and whether drugs already in use for other indications and that interact with the Sigma-1 receptor might also prevent oxidative damage due to conditions such as cerebral ischemic stroke. The antipsychotic drug haloperidol is an antagonist of Sigma-1 receptors and in this study it potently protects against oxidative stress-related cell death in vitro at low concentrations. The protective potency of haloperidol and a number of other butyrophenone compounds positively correlate with their affinity for a cloned Sigma-1 receptor, and the protection is mimicked by a Sigma-1 receptor-selective antagonist (BD1063), but not an agonist (PRE-084). In vivo, an acute low dose (0.05 mg/kg s.c.) of haloperidol reduces by half the ischemic lesion volume induced by a transient middle cerebral artery occlusion. These in vitro and in vivo pre-clinical results suggest that a low dose of acutely administered haloperidol might have a novel application as a protective agent against ischemic cerebral stroke and other types of brain injury with an ischemic component.
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PMID:A prototypical Sigma-1 receptor antagonist protects against brain ischemia. 1791 67

In adult stroke models, 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP), a sigma receptor agonist, attenuates activity of neuronal nitric oxide synthase (nNOS), blunts ischemia-induced nitric oxide production, and provides neuroprotection. Here, we tested the hypothesis that PPBP attenuates neuronal damage in a model of global hypoxia-ischemia (H-I) in newborn piglets. Piglets subjected to hypoxia followed by asphyxic cardiac arrest were treated with saline or two dosing regimens of PPBP after resuscitation. Sigma-1 receptors were found in striatal neurons. PPBP dose-dependently protected neurons in putamen at 4 days of recovery from H-I. Immunoblots of putamen extracts at 3 h of recovery showed that PPBP decreased H-I-induced recruitment of nNOS in the membrane fraction and reduced the association of nNOS with NMDA receptor NR2 subunit. The latter effect was associated with changes in the coupling of nNOS to postsynaptic density-95 (PSD-95), but not NR2-PSD-95 interactions. Moreover, PPBP suppressed NOS activity in the membrane fraction and reduced H-I-induced nitrative and oxidative damage to proteins and nucleic acids. These findings indicate that PPBP protects striatal neurons in a large animal model of neonatal H-I and that the protection is associated with decreased coupling of nNOS to PSD-95.
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PMID:Sigma receptor ligand 4-phenyl-1-(4-phenylbutyl)-piperidine modulates neuronal nitric oxide synthase/postsynaptic density-95 coupling mechanisms and protects against neonatal ischemic degeneration of striatal neurons. 1988 43