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. Export

@article{citeulike:6071694, abstract = {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.}, author = {Yang, Zeng-Jin J. and Carter, Erin L. and Torbey, Michel T. and Martin, Lee J. and Koehler, Raymond C.}, citeulike-article-id = {6071694}, citeulike-linkout-0 = {http://dx.doi.org/10.1016/j.expneurol.2009.10.019}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/19883643}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=19883643}, day = {30}, doi = {10.1016/j.expneurol.2009.10.019}, issn = {1090-2430}, journal = {Experimental neurology}, keywords = {4-phenyl-1-4-phenylbutyl-piperidine, against, and, coupling, degeneration, density-95, ischemic, ligand, mechanisms, modulates, neonatal, neuronal, neurons, nitric, of, oxide, protects, receptor, sigma, striatal, synthase-postsynaptic}, month = {October}, posted-at = {2009-11-04 22:31:00}, priority = {2}, title = {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.}, url = {http://dx.doi.org/10.1016/j.expneurol.2009.10.019}, year = {2009} }

TY - JOUR ID - citeulike:6071694 L3 - citeulike-article-id:6071694 N2 - 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. JF - Experimental neurology SN - 1090-2430 TI - 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. KW - 4-phenyl-1-4-phenylbutyl-piperidine KW - against KW - and KW - coupling KW - degeneration KW - density-95 KW - ischemic KW - ligand KW - mechanisms KW - modulates KW - neonatal KW - neuronal KW - neurons KW - nitric KW - of KW - oxide KW - protects KW - receptor KW - sigma KW - striatal KW - synthase-postsynaptic AU - Yang, Zeng-Jin AU - Carter, Erin AU - Torbey, Michel AU - Martin, Lee AU - Koehler, Raymond PY - 2009/10/30/ UR - http://dx.doi.org/10.1016/j.expneurol.2009.10.019 ER -