TY - JOUR
T1 - In vivo protection against retinal neurodegeneration by sigma receptor 1 ligand (+)-pentazocine
AU - Smith, Sylvia B.
AU - Duplantier, Jennifer
AU - Dun, Ying
AU - Mysona, Barbara
AU - Roon, Penny
AU - Martin, Pamela M.
AU - Ganapathy, Vadivel
PY - 2008/9
Y1 - 2008/9
N2 - PURPOSE. To evaluate the neuroprotective properties of the sigma receptor 1 (σR1) ligand, (+)-pentazocine in an in vivo model of retinal neurodegeneration. METHODS. Spontaneously diabetic Ins2Akita/+ and wild-type mice received intraperitoneal injections of (+)-pentazocine for 22 weeks beginning at diabetes onset. Retinal mRNA and protein were analyzed by RT-PCR and Western blot analysis. Retinal histologic sections were measured to determine total retinal thickness, thicknesses of inner- outer nuclear and plexiform layers (INL, ONL, IPL, INL), and the number of cell bodies in the ganglion cell layer (GCL). Immunolabeling experiments were performed using antibodies specific for 4-hydroxynonenal and nitrotyrosine, markers of lipid peroxidation, and reactive nitrogen species, respectively, and an antibody specific for vimentin to view radial Müller fibers. RESULTS. σR1 mRNA and protein levels in the Ins2Akita/+ retina were comparable to those in the wild-type, indicating that σR1 is an available target during the disease process. Histologic evaluation of eyes of Ins2Akita/+ mice showed disruption of retinal architecture. By 17 to 25 weeks after birth, Ins2Akita/+ mice demonstrated ∼30% and 25% decreases in IPL and INL thicknesses, respectively, and a 30% reduction in ganglion cells. In the (+)-pentazocine-treated group, retinas of Ins2Akita/+ mice showed remarkable preservation of retinal architecture; IPL and INL thicknesses of (+)-pentazocine-treated Ins2Akita/+ mouse retinas were within normal limits. The number of ganglion cells was 15.6 ± 1.5 versus 10.4 ± 1.2 cells/100 μm retinal length in (+)-pentazocine-treated versus nontreated mutant mice. Levels of nitrotyrosine and 4-hydroxynonenal increased in Ins2 Akita/+ retinas, but were reduced in (+)-pentazocine-treated mice. Retinas of Ins2Akita/+ mice showed loss of the uniform organization of radial Müller fibers. Retinas of (+)-pentazocine-treated mice maintained the radial organization of glial processes. CONCLUSION. Sustained (+)-pentazocine treatment in an in vivo model of retinal degeneration conferred significant neuroprotection, reduced evidence of oxidative stress, and preserved retinal architecture, suggesting that σR1 ligands are promising therapeutic agents for intervention in neurodegenerative diseases of the retina.
AB - PURPOSE. To evaluate the neuroprotective properties of the sigma receptor 1 (σR1) ligand, (+)-pentazocine in an in vivo model of retinal neurodegeneration. METHODS. Spontaneously diabetic Ins2Akita/+ and wild-type mice received intraperitoneal injections of (+)-pentazocine for 22 weeks beginning at diabetes onset. Retinal mRNA and protein were analyzed by RT-PCR and Western blot analysis. Retinal histologic sections were measured to determine total retinal thickness, thicknesses of inner- outer nuclear and plexiform layers (INL, ONL, IPL, INL), and the number of cell bodies in the ganglion cell layer (GCL). Immunolabeling experiments were performed using antibodies specific for 4-hydroxynonenal and nitrotyrosine, markers of lipid peroxidation, and reactive nitrogen species, respectively, and an antibody specific for vimentin to view radial Müller fibers. RESULTS. σR1 mRNA and protein levels in the Ins2Akita/+ retina were comparable to those in the wild-type, indicating that σR1 is an available target during the disease process. Histologic evaluation of eyes of Ins2Akita/+ mice showed disruption of retinal architecture. By 17 to 25 weeks after birth, Ins2Akita/+ mice demonstrated ∼30% and 25% decreases in IPL and INL thicknesses, respectively, and a 30% reduction in ganglion cells. In the (+)-pentazocine-treated group, retinas of Ins2Akita/+ mice showed remarkable preservation of retinal architecture; IPL and INL thicknesses of (+)-pentazocine-treated Ins2Akita/+ mouse retinas were within normal limits. The number of ganglion cells was 15.6 ± 1.5 versus 10.4 ± 1.2 cells/100 μm retinal length in (+)-pentazocine-treated versus nontreated mutant mice. Levels of nitrotyrosine and 4-hydroxynonenal increased in Ins2 Akita/+ retinas, but were reduced in (+)-pentazocine-treated mice. Retinas of Ins2Akita/+ mice showed loss of the uniform organization of radial Müller fibers. Retinas of (+)-pentazocine-treated mice maintained the radial organization of glial processes. CONCLUSION. Sustained (+)-pentazocine treatment in an in vivo model of retinal degeneration conferred significant neuroprotection, reduced evidence of oxidative stress, and preserved retinal architecture, suggesting that σR1 ligands are promising therapeutic agents for intervention in neurodegenerative diseases of the retina.
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U2 - 10.1167/iovs.08-1824
DO - 10.1167/iovs.08-1824
M3 - Article
C2 - 18469181
AN - SCOPUS:53149105545
SN - 0146-0404
VL - 49
SP - 4154
EP - 4161
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
IS - 9
ER -