Neuroimmunophilin Ligands Protect Cavernous Nerves after Crush Injury in the Rat: New Experimental Paradigms

Heather Valentine, Yi Chen, Hongzhi Guo, Jocelyn McCormick, Yong Wu, Sena F. Sezen, Ahmet Hoke, Arthur L. Burnett, Joseph P. Steiner

Research output: Contribution to journalArticle

Abstract

Objectives: We investigated the effects of the orally bioavailable non-immunosuppressive immunophilin ligand GPI 1046 (GPI) on erectile function and cavernous nerve (CN) histology following unilateral or bilateral crush injury (UCI, BCI, respectively) of the CNs. Methods: Adult male Sprague-Dawley rats were administered GPI 15 mg/kg intraperitoneally (ip) or 30 mg/kg orally (po), FK506 1 mg/kg, ip, or vehicle controls for each route of administration just prior to UCI or BCI and daily up to 7 d following injury. At day 1 or 7 of treatment, erectile function induced by CN electrical stimulation was measured, and electron microscopic analysis of the injured CN was performed. Results: Intraperitoneal administration of GPI to rats with injured CN protected erectile function, in a fashion similar to the prototypic immunophilin ligand FK506, compared with vehicle-treated animals (93% ± 9% vs. 70% ± 5% vs. 45% ± 1%, p < 0.01, respectively). Oral administration of GPI elicited the same level of significant protection from CN injury. GPI administered po at 30 mg/kg/d, dosing either once daily or four times daily with 7.5 mg/kg, provided nearly complete protection of erectile function. In a more severe BCI model, po administration of GPI maintained erectile function at 24 h after CN injury. Ultrastructural analysis of injured CNs indicated that GPI administered at the time of CN injury prevents degeneration of about 83% of the unmyelinated axons at 7 d after CN injury. Conclusions: The orally administered immunophilin ligand GPI neuroprotects CNs and maintains erectile function in rats under various conditions of CN crush injury.

Original languageEnglish (US)
Pages (from-to)1724-1731
Number of pages8
JournalEuropean Urology
Volume51
Issue number6
DOIs
StatePublished - Jun 2007

Keywords

  • Cavernous nerve injury
  • Erectile dysfunction
  • Immunophilin ligands

ASJC Scopus subject areas

  • Urology

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