Potent sigma1-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine modulates basal and N-methyl-D-aspartate-evoked nitric oxide production in vivo.
OBJECTIVE
final sigma-Receptor ligands ameliorate ischemic neuronal injury and modulate neuronal responses to N-methyl-D-aspartate (NMDA) receptor stimulation. Because NMDA-evoked synthesis of nitric oxide (NO) may play an important role in excitotoxic-mediated injury, we tested the hypothesis that final sigma-receptor ligands attenuate basal and NMDA-evoked NO production in the striatum in vivo.


METHODS
Microdialysis probes were placed bilaterally into the striatum of halothane-anesthetized adult Wistar rats. Rats were divided into 7 treatment groups and perfused with artificial cerebrospinal fluid (aCSF) containing 3 micromol/L [14C]L-arginine for 2 to 3 hours followed by NMDA in various combinations with the following drugs: L-nitroarginine (L-NNA); the final sigma1-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP); the selective final sigma1-receptor antagonist 1-(cyclopropylmethyl)-4-(2'-oxoethyl) piperidine hydrobromide (DuP 734); and the noncompetitive NMDA receptor blocker MK-801 in aCSF. Right-left differences between [14C]L-citrulline in the effluent from rats treated with different drug combinations were assumed to reflect differences in NO production.


RESULTS
After a 3-hour loading period with [14C]L-arginine, addition of 1 mmol/L NMDA increased [14C]L-citrulline recovery compared with aCSF alone. This NMDA-evoked increase was inhibited by 1 mmol/L of L-NNA and PPBP. Perfusion of 1 mmol/L of the final sigma1-receptor antagonist DuP 734 with 1 mmol/L PPBP augmented NMDA-evoked [14C]L-citrulline recovery compared with perfusion with PPBP and NMDA. MK-801 attenuated the basal as well as NMDA-evoked [14C]L-citrulline recovery. PPBP did not cause any further attenuation in the basal and NMDA-evoked [14C]L-citrulline recovery in the presence of MK-801.


CONCLUSIONS
These data indicate that a final sigma1-receptor ligand attenuates basal as well as NMDA-evoked NO production. Because the attenuated NO production was reversed by DuP 734, PPBP appears to act as an agonist at the final sigma1-receptor. Attenuated NO production by final sigma1-receptor agonists provides one possible mechanism for focal ischemic neuroprotection.
Bhardwaj
A
A
Department of Neurology, Johns Hopkins University School of Medicine, and National Institute on Drug Abuse, Baltimore, MD 21287, USA. abhardwa@welchlink.welch.jhu.edu
Sawada
M
M
London
E D
ED
Koehler
R C
RC
Traystman
R J
RJ
Kirsch
J R
JR
D000818:Animals; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D002250:Carbon Radioisotopes; D002956:Citrulline / Q000493:pharmacokinetics; D004268:DNA-Binding Proteins / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019476:Insect Proteins; D008297:Male; D017551:Microdialysis; D016202:N-Methylaspartate / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019335:Nitroarginine / Q000494:pharmacology; D009687:Nuclear Proteins / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D017480:Receptors, sigma / Q000502:physiology*
D002250:Carbon Radioisotopes; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D019476:Insect Proteins; D009687:Nuclear Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; C085605:polyhedrin promoter-binding protein, insect; D019335:Nitroarginine; D002956:Citrulline; D009569:Nitric Oxide; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate