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 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

Fingerprint

Nerve Crush
Immunophilins
Ligands
Wounds and Injuries
Tacrolimus
Electric Stimulation
Oral Administration
Sprague Dawley Rats
Axons
Histology
Crush Injuries
Electrons

Keywords

  • Cavernous nerve injury
  • Erectile dysfunction
  • Immunophilin ligands

ASJC Scopus subject areas

  • Urology

Cite this

Valentine, H., Chen, Y., Guo, H., McCormick, J., Wu, Y., Sezen, S. F., ... Steiner, J. P. (2007). Neuroimmunophilin Ligands Protect Cavernous Nerves after Crush Injury in the Rat: New Experimental Paradigms. European Urology, 51(6), 1724-1731. https://doi.org/10.1016/j.eururo.2006.11.026

Neuroimmunophilin Ligands Protect Cavernous Nerves after Crush Injury in the Rat : New Experimental Paradigms. / Valentine, Heather; Chen, Yi; Guo, Hongzhi; McCormick, Jocelyn; Wu, Yong; Sezen, Sena F.; Hoke, Ahmet; Burnett, Arthur; Steiner, Joseph P.

In: European Urology, Vol. 51, No. 6, 06.2007, p. 1724-1731.

Research output: Contribution to journalArticle

Valentine, Heather ; Chen, Yi ; Guo, Hongzhi ; McCormick, Jocelyn ; Wu, Yong ; Sezen, Sena F. ; Hoke, Ahmet ; Burnett, Arthur ; Steiner, Joseph P. / Neuroimmunophilin Ligands Protect Cavernous Nerves after Crush Injury in the Rat : New Experimental Paradigms. In: European Urology. 2007 ; Vol. 51, No. 6. pp. 1724-1731.
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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.",
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T2 - New Experimental Paradigms

AU - Valentine, Heather

AU - Chen, Yi

AU - Guo, Hongzhi

AU - McCormick, Jocelyn

AU - Wu, Yong

AU - Sezen, Sena F.

AU - Hoke, Ahmet

AU - Burnett, Arthur

AU - Steiner, Joseph P.

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N2 - 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.

AB - 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.

KW - Cavernous nerve injury

KW - Erectile dysfunction

KW - Immunophilin ligands

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