title: FK506 neuroprotection after cavernous nerve injury is mediated by thioredoxin and glutathione redox systems.
abstract: BACKGROUND
  Immunophilin ligands such as FK506 (FK) preserve erectile function (EF) following cavernous nerve injury (CNI), although the precise mechanisms are unclear. We examined whether the thioredoxin (Trx) and glutathione (GSH) redox systems mediate this effect after CNI.
  
  
  OBJECTIVE
  To investigate the roles of Trx reductase 2 (TrxR2) and S-Nitrosoglutathione reductase (GSNOR) as antioxidative/nitrosative and antiapoptotic mediators of the neuroprotective effect of FK in the penis after CNI.
  
  
  METHODS
  Adult male rats, wild-type (WT) mice, and GSNOR deficient (GSNOR -/-) mice were divided into four groups: sham surgery (CN [cavernous nerves] exposure only) + vehicle; sham surgery + FK (5 mg/kg/day/rat or 2 mg/kg/day/mouse, for 2 days, subcutaneous); CNI + vehicle; and CNI + FK. At day 4 after injury, electrically stimulated changes in intracavernosal pressure (ICP) were measured. Penises were collected for Western blot analysis of TrxR2, GSNOR, and Bcl-2, and for immunolocalization of TrxR2 and GSNOR.
  
  
  METHODS
  EF assessment represented by maximal ICP and total ICP in response to electrical stimulation. Evaluation of protein expression levels and distribution patterns of antioxidative/nitrosative and antiapoptotic factors in penile tissue.
  
  
  RESULTS
  EF decreased after CNI compared with sham surgery values in both rats (P < 0.01) and WT and GSNOR -/- mice (P < 0.05). FK treatment preserved EF after CNI compared with vehicle treatment in rats (P < 0.01) and WT mice (P < 0.05) but not in GSNOR -/- mice. In rats, GSNOR (P < 0.01) and Bcl-2 (P < 0.05) expressions were significantly decreased after CNI. FK treatment in CN-injured rats restored expression of GSNOR and upregulated TrxR2 (P < 0.001) and Bcl-2 (P < 0.001) expressions compared with vehicle treatment. Localizations of proteins in the penis were observed for TrxR2 (endothelium, smooth muscle) and for GSNOR (nerves, endothelium, smooth muscle).
  
  
  CONCLUSIONS
  The neuroprotective effect of FK in preserving EF after CNI involves antioxidative/nitrosative and antiapoptotic mechanisms mediated, to some extent, by Trx and GSH systems.
authors: Department of Urology, The James Buchanan Brady Urological Institute, The Johns Hopkins Hospital and The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Gwen
authors: G
authors: Lagoda
authors: Yi
authors: Y
authors: Xie
authors: Sena F
authors: SF
authors: Sezen
authors: K Joseph
authors: KJ
authors: Hurt
authors: Limin
authors: L
authors: Liu
authors: Biljana
authors: B
authors: Musicki
authors: Arthur L
authors: AL
authors: Burnett
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010413:Penis / Q000293:injuries* / Q000294:innervation; D011453:Prostaglandins / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013223:Statistics as Topic; D016559:Tacrolimus / Q000494:pharmacology* / Q000627:therapeutic use; D054482:Thioredoxin Reductase 2 / Q000187:drug effects; D013879:Thioredoxins / Q000378:metabolism*
chemical_list: D007166:Immunosuppressive Agents; D018696:Neuroprotective Agents; D011453:Prostaglandins; D013879:Thioredoxins; D000445:Aldehyde Oxidoreductases; C087006:formaldehyde dehydrogenase, glutathione-independent; C516127:TXNRD2 protein, human; D054482:Thioredoxin Reductase 2; D005978:Glutathione; D016559:Tacrolimus