title: Neuroprotective effects of tempol acyl esters against retinal ganglion cell death in a rat partial optic nerve crush model.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Centre for Ophthalmology, University of Tuebingen, Tuebingen, Germany. sebastian.thaler@uni-tuebingen.de
authors.forename: Sebastian
authors.initials: S
authors.lastname: Thaler
authors.forename: Michal
authors.initials: M
authors.lastname: Fiedorowicz
authors.forename: Pawel
authors.initials: P
authors.lastname: Grieb
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Wypych
authors.forename: Narcyz
authors.initials: N
authors.lastname: Knap
authors.forename: Tomasz
authors.initials: T
authors.lastname: Borowik
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Zawada
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Kaminski
authors.forename: Michal
authors.initials: M
authors.lastname: Wozniak
authors.forename: Robert
authors.initials: R
authors.lastname: Rejdak
authors.forename: Eberhart
authors.initials: E
authors.lastname: Zrenner
authors.forename: Frank
authors.initials: F
authors.lastname: Schuettauf
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004578:Electron Spin Resonance Spectroscopy; D004735:Energy Transfer; D004952:Esters / Q000737:chemistry; D016166:Free Radical Scavengers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008081:Liposomes; D009409:Nerve Crush; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009900:Optic Nerve / Q000473:pathology*; D051381:Rats; D011914:Rats, Inbred BN; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013113:Spin Labels / Q000138:chemical synthesis
chemical_list: D003497:Cyclic N-Oxides; D004952:Esters; D016166:Free Radical Scavengers; D008081:Liposomes; D018696:Neuroprotective Agents; D013113:Spin Labels; C001803:tempol