Neuroprotective effects of tempol acyl esters against retinal ganglion cell death in a rat partial optic nerve crush model
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Neuroprotective effects of tempol acyl esters against retinal ganglion cell death in a rat partial optic nerve crush model. / Thaler, Sebastian; Fiedorowicz, Michal; Grieb, Pawel; Wypych, Zbigniew; Knap, Narcyz; Borowik, Tomasz; Zawada, Katarzyna; Kaminski, Jaroslaw; Wozniak, Michal; Rejdak, Robert; Zrenner, Eberhart; Schuettauf, Frank.
in: ACTA OPHTHALMOL, Jahrgang 89, Nr. 7, 11.2011, S. e555-60.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Neuroprotective effects of tempol acyl esters against retinal ganglion cell death in a rat partial optic nerve crush model
AU - Thaler, Sebastian
AU - Fiedorowicz, Michal
AU - Grieb, Pawel
AU - Wypych, Zbigniew
AU - Knap, Narcyz
AU - Borowik, Tomasz
AU - Zawada, Katarzyna
AU - Kaminski, Jaroslaw
AU - Wozniak, Michal
AU - Rejdak, Robert
AU - Zrenner, Eberhart
AU - Schuettauf, Frank
N1 - © 2011 The Authors. Acta Ophthalmologica © 2011 Acta Ophthalmologica Scandinavica Foundation.
PY - 2011/11
Y1 - 2011/11
N2 - PURPOSE: The aim of this study is to search for more effective derivatives of the superoxide dismutase mimetic tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl). Although tempol is neuroprotective in a rat partial optic nerve crush (PONC) model, relatively high doses are required to exert this effect.METHODS: Tempol acyl esters with different-length fatty acids (tempol-C4, tempol-C8, tempol-C12 and tempol-C16) were synthesized and the following properties were evaluated: water-octanol partition coefficient, liposome-liposome energy transfer, and electron paramagnetic resonance (EPR). Brown Norway rats underwent PONC and received tempol or acyl esters intraperitoneally once daily for 7 consecutive days. We then compared the effects of tempol and its four esters on retinal ganglion cell (RGC) damage using a retrograde labelling method.RESULTS: The water-octanol partition coefficient increased with increasing length of attached acyl chain. However, the energy of the liposome-liposome transfer seemed to be optimal for tempol-C8 and tempol-C12. The EPR signal was very similar for all tested compounds, suggesting similar efficiency of superoxide scavenging. Partial optic nerve crush in vehicle-treated animals reduced RGC numbers by approx. 59% when compared with sham-operated eyes. Tempol did not affect RGC loss at a dose of 1 mg/kg. In contrast, at molar doses equivalent to 1 mg/kg of tempol, tempol-C8 showed a significant neuroprotective effect, whereas tempol-C4, tempol-C12 and tempol-C16 did not act neuroprotectively.CONCLUSION: Manipulating the hydrophobicity of tempol seems to be a promising tool for developing more potent neuroprotectants in the PONC degeneration model. However, the resulting compounds need further pharmacological evaluation.
AB - PURPOSE: The aim of this study is to search for more effective derivatives of the superoxide dismutase mimetic tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl). Although tempol is neuroprotective in a rat partial optic nerve crush (PONC) model, relatively high doses are required to exert this effect.METHODS: Tempol acyl esters with different-length fatty acids (tempol-C4, tempol-C8, tempol-C12 and tempol-C16) were synthesized and the following properties were evaluated: water-octanol partition coefficient, liposome-liposome energy transfer, and electron paramagnetic resonance (EPR). Brown Norway rats underwent PONC and received tempol or acyl esters intraperitoneally once daily for 7 consecutive days. We then compared the effects of tempol and its four esters on retinal ganglion cell (RGC) damage using a retrograde labelling method.RESULTS: The water-octanol partition coefficient increased with increasing length of attached acyl chain. However, the energy of the liposome-liposome transfer seemed to be optimal for tempol-C8 and tempol-C12. The EPR signal was very similar for all tested compounds, suggesting similar efficiency of superoxide scavenging. Partial optic nerve crush in vehicle-treated animals reduced RGC numbers by approx. 59% when compared with sham-operated eyes. Tempol did not affect RGC loss at a dose of 1 mg/kg. In contrast, at molar doses equivalent to 1 mg/kg of tempol, tempol-C8 showed a significant neuroprotective effect, whereas tempol-C4, tempol-C12 and tempol-C16 did not act neuroprotectively.CONCLUSION: Manipulating the hydrophobicity of tempol seems to be a promising tool for developing more potent neuroprotectants in the PONC degeneration model. However, the resulting compounds need further pharmacological evaluation.
KW - Animals
KW - Cell Survival/drug effects
KW - Cyclic N-Oxides/chemical synthesis
KW - Disease Models, Animal
KW - Electron Spin Resonance Spectroscopy
KW - Energy Transfer
KW - Esters/chemistry
KW - Free Radical Scavengers/chemical synthesis
KW - Injections, Intraperitoneal
KW - Liposomes
KW - Nerve Crush
KW - Nerve Degeneration/metabolism
KW - Neuroprotective Agents/chemical synthesis
KW - Optic Nerve/pathology
KW - Rats
KW - Rats, Inbred BN
KW - Retinal Ganglion Cells/drug effects
KW - Spin Labels/chemical synthesis
U2 - 10.1111/j.1755-3768.2011.02180.x
DO - 10.1111/j.1755-3768.2011.02180.x
M3 - SCORING: Journal article
C2 - 21645284
VL - 89
SP - e555-60
JO - ACTA OPHTHALMOL
JF - ACTA OPHTHALMOL
SN - 1755-375X
IS - 7
ER -
