Neuroprotective Effect of σ ₁ -Receptor Ligand 4-Phenyl-1-(4-Phenylbutyl) Piperidine (PPBP) Is Linked to Reduced Neuronal Nitric Oxide Production

Abstract

Background and Purpose-The potent 1 -receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) provides neuroprotection in experimental stroke. We tested the hypothesis that PPBP attenuates striatal tissue damage after middle cerebral artery occlusion (MCAO) by a mechanism involving reduction of ischemia-evoked nitric oxide (NO) production. Furthermore, we determined whether the agent fails to protect ischemic brain when neuronal nitric oxide synthase (nNOS) is genetically deleted or pharmacologically inhibited (selective nNOS inhibitor, 7-nitroindazole [7-NI]). Methods-Halothane-anesthetized adult male Wistar rats were subjected to 2 hours of MCAO by the intraluminal filament occlusion technique. All physiological variables were controlled during the ischemic insult. In vivo striatal NO production was estimated via microdialysis by quantification of local, labeled citrulline recovery after labeled arginine infusion. In a second series of experiments, nNOS null mutants (nNOSKOs) and the genetically matched wild-type (WT) strain were treated with 90 minutes of MCAO. Brains were harvested at 22 hours of reperfusion for measurement of infarction volume by triphenyltetrazolium chloride histology. Results-PPBP attenuated infarction volume at 22 hours of reperfusion in cerebral cortex and striatum and markedly attenuated NO production in ischemic and nonischemic striatum during occlusion and early reperfusion. Treatment with 7-NI mimicked the effects of PPBP. In WT mice, infarction volume was robustly decreased by both PPBP and 7-NI, but the efficacy of PPBP was not altered by pharmacological nNOS inhibition in combined therapy. In contrast, PPBP did not decrease infarction volume in nNOSKO mice. Conclusions-These data suggest that the mechanism of neuroprotection of PPBP in vivo is through attenuation of nNOS activity and ischemia-evoked NO production. Neuroprotective effects of PPBP are lost when nNOS is not present or is inhibited; therefore, PPBP likely acts upstream from NO generation and its subsequent neurotoxicity. (Stroke. 2001;32: 1613-1620.)

The sigma receptor ligand (+)−pentazocine prevents apoptotic retinal ganglion cell death induced in vitro by homocysteine and glutamate

“…σR1 ligands have broad neuroprotective effects. They not only reduce NMDA receptor activation [5,34], but also can inhibit ischemia-induced glutamate release [27,28], attenuate postsynaptic glutamate-evoked Ca 2+ influx [10,20], and reduce NO production [14]. These beneficial effects of σR1 ligands are noteworthy for diseases in which ganglion cells die, such as in glaucoma [24,25] and, as has been reported recently, in diabetic retinopathy [2,12,15,55].…”

“…The neuroprotective effects of σR1 ligands are thought to include modulation of NMDA receptors as well as muscarinic receptors [5,35]. Sigma receptor ligands demonstrate robust neuroprotective properties including inhibition of ischemia-induced glutamate release [27,28], attenuation of postsynaptic glutamate-evoked calcium influx [10,20], depressed neuronal responsivity to NMDA receptor stimulation [3,7,54], and reduced NO production [14].…”

Ischemic Nitric Oxide and Poly (ADP-Ribose) Polymerase-1 in Cerebral Ischemia: Male Toxicity, Female Protection

“…7NI and PJ-34 are among the most specific inhibitors available for nNOS and PARP, respectively, and both greatly exacerbate ischemic damage selectively in females. Doses administered in the study were based on efficacy in previous experiments in males, and we did not examine a full range of doses in these experiments (Goyagi et al, 2001;Abdelkarim et al, 2001;Coert et al, 1999). While it is possible that pharmacokinetics for these agents differ by sex, it seems unlikely that such a factor could explain the combined and perfectly consistent observations in knockouts and drug-treated cohorts.…”

An α-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain

“…Ten ␣-Syn Ϫ/Ϫ mice and 10 WT mice with body weights of 27-32 g were anesthetized with 1-1.2% halothane in oxygen-enriched air, and rectal temperatures were controlled at 37 Ϯ 0.5°C with heating lamps during the entire surgical procedure. Mice were then subjected to unilateral middle cerebral artery occlusion in a randomized fashion (7)(8)(9). In brief, a 5-0 nylon monofilament was inserted via an external carotid artery stump to a point 6-mm distal to the internal carotid artery͞pterygopalatine bifurcation, and the common carotid was temporarily occluded with a 6-0 nylon suture.…”