(Stroke. 2001;32:1613.)
© 2001 American Heart Association, Inc.
Original Contributions |
Neuroprotective Effect of 
1-Receptor Ligand 4-Phenyl-1-(4-Phenylbutyl) Piperidine (PPBP) Is Linked to Reduced Neuronal Nitric Oxide Production
From the Departments of Anesthesiology and Critical Care Medicine (T.G., S.G., A.B., P.D.H., J.R.K.), Neurology (A.B., J.R.K.), and Neuroscience (V.L.D.), Johns Hopkins University School of Medicine, Baltimore, Md. Drs Goyagi and Goto have contributed equally as primary authors.
Correspondence to Anish Bhardwaj, MD, Neurosciences Critical Care Division, Meyer 8-140, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287. E-mail abhardwa{at}jhmi.edu
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.
Key Words: cerebral ischemia, focal • excitotoxicity • infarction • nitric oxide • receptors, sigma • reperfusion
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