Potent sigma1-Receptor Ligand 4-Phenyl-1-(4-Phenylbutyl) Piperidine Modulates Basal and N-Methyl-D-Aspartate-Evoked Nitric Oxide Production In Vivo

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Abstract

Background and Purpose

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 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 [micro sign]mol/L [(14) C]L-arginine for 2 to 3 hours followed by NMDA in various combinations with the following drugs: L-nitroarginine (L-NNA); the sigma1-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP); the selective sigma1-receptor antagonist 1-(cyclopropylmethyl)-4-(2[prime]-oxoethyl) piperidine hydrobromide (DuP 734); and the noncompetitive NMDA receptor blocker MK-801 in aCSF. Right-left differences between [(14) C]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 [(14) C]L-arginine, addition of 1 mmol/L NMDA increased [(14) C]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 sigma1-receptor antagonist DuP 734 with 1 mmol/L PPBP augmented NMDA-evoked [(14) C]L-citrulline recovery compared with perfusion with PPBP and NMDA. MK-801 attenuated the basal as well as NMDA-evoked [(14) C]L-citrulline recovery. PPBP did not cause any further attenuation in the basal and NMDA-evoked [(14) C]L-citrulline recovery in the presence of MK-801.

Conclusions

These data indicate that a 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 sigma1-receptor. Attenuated NO production by sigma1-receptor agonists provides one possible mechanism for focal ischemic neuroprotection. (Stroke. 1998;29:2404-2411.)

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