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.
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.
Yang
Zeng-Jin
ZJ
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. zyang4@jhmi.edu
Carter
Erin L
EL
Torbey
Michel T
MT
Martin
Lee J
LJ
Koehler
Raymond C
RC
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002545:Brain Ischemia / Q000150:complications; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D047468:Immunoprecipitation / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009410:Nerve Degeneration / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D017480:Receptors, sigma / Q000187:drug effects; D013552:Swine
D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D018492:Dopamine Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; C094850:4-phenyl-1-(4-phenylbutyl)piperidine; D052248:Nitric Oxide Synthase Type I; D006220:Haloperidol