Sonic hedgehog regulation of cavernous nerve regeneration and neurite formation in aged pelvic plexus

Ryan Dobbs, Elizabeth Kalmanek, Shawn Choe, Daniel A Harrington, Samuel I. Stupp, Kevin T. McVary, Carol A. Podlasek

Research output: Contribution to journalArticle

Abstract

Introduction: Erectile dysfunction (ED) is a significant health concern that greatly impacts quality of life, and is common in men as they age, impacting 52% of men between the ages of 40 and 70. A significant underlying cause of ED development is injury to the cavernous nerve (CN), a peripheral nerve that innervates the penis. CN injury also occurs in up to 82% of prostatectomy patients. We recently showed that Sonic hedgehog (SHH) protein delivered by peptide amphiphile (PA) nanofiber hydrogel to the CN and penis of a prostatectomy model of CN injury, is neuroprotective, accelerates CN regeneration, improves erectile function ~60%, preserves penile smooth muscle 56% and suppresses collagen deposition 30%. This regenerative potential is substantial in an adult prostatectomy model (P120). However prostatectomy patients are typically older (61.5 ± 9.6 years) and our models should mimic patient conditions more effectively when considering translation. In this study we examine regenerative potential in an aged prostatectomy model (P200–329). Methods: The caudal portion of the pelvic ganglia (MPG) and CN were dissected from adult (n = 11), and aged (n = 13) Sprague Dawley rats, and were grown in organ culture 3 days. Uninjured and 2 day CN crushed MPG/CN were exposed to Affi-Gel beads containing SHH protein, PBS (control), or 5e1 SHH inhibitor. Neurites were quantified by counting the number of growth cones normalized by tissue perimeter (mm) and immunohistochemistry for SHH, patched1 (PTCH1), smoothened (SMO), GLI1-3, and GAP43 were performed. Results: SHH treatment increased neurites 3.5-fold, in uninjured adult, and 5.7-fold in aged rats. Two days after CN crush, SHH treatment increased neurites 1.8-fold in adult rats and 2.5-fold in aged rats. SHH inhibition inhibited neurite formation in uninjured MPG/CN but not in 2 day CN crushed MPG/CN. PTCH1 and SMO (SHH receptors), and SHH transcriptional activators/repressors, GLI1-3, were abundant in aged MPG/CN with unaltered localization. ROCK1 was induced with SHH treatment. Conclusions: Reintroduction of SHH protein in an aged prostatectomy model is even more effective in promoting neurite formation/CN regeneration than in the adult. The first 48 h after CN injury are a critical window when growth factors are released, that impact later neurite formation. These studies are significant because most prostatectomy patients are not young and healthy, as with adult rats, so the aged prostatectomy model will more accurately simulate ED patient response. Understanding how neurite formation changes with age is critical for clinical translation of SHH PA to prostatectomy patients.

LanguageEnglish
Pages10-19
Number of pages10
JournalExperimental Neurology
Volume312
DOIs
StatePublished - Feb 1 2019

Fingerprint

Hypogastric Plexus
Nerve Regeneration
Hedgehogs
Neurites
Prostatectomy
Hedgehog Proteins
Erectile Dysfunction
Penis
Wounds and Injuries
Nerve Crush
Nanofibers
Growth Cones
Peptides
Hydrogel
Organ Culture Techniques
Peripheral Nerves
Ganglia
Smooth Muscle
Sprague Dawley Rats
Intercellular Signaling Peptides and Proteins

Keywords

  • Aging
  • Cavernous nerve regeneration
  • Neurite
  • Prostatectomy
  • Sonic hedgehog

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

Cite this

Dobbs, R., Kalmanek, E., Choe, S., Harrington, D. A., Stupp, S. I., McVary, K. T., & Podlasek, C. A. (2019). Sonic hedgehog regulation of cavernous nerve regeneration and neurite formation in aged pelvic plexus. Experimental Neurology, 312, 10-19. https://doi.org/10.1016/j.expneurol.2018.11.001

Sonic hedgehog regulation of cavernous nerve regeneration and neurite formation in aged pelvic plexus. / Dobbs, Ryan; Kalmanek, Elizabeth; Choe, Shawn; Harrington, Daniel A; Stupp, Samuel I.; McVary, Kevin T.; Podlasek, Carol A.

In: Experimental Neurology, Vol. 312, 01.02.2019, p. 10-19.

Research output: Contribution to journalArticle

Dobbs, R, Kalmanek, E, Choe, S, Harrington, DA, Stupp, SI, McVary, KT & Podlasek, CA 2019, 'Sonic hedgehog regulation of cavernous nerve regeneration and neurite formation in aged pelvic plexus' Experimental Neurology, vol. 312, pp. 10-19. https://doi.org/10.1016/j.expneurol.2018.11.001
Dobbs, Ryan ; Kalmanek, Elizabeth ; Choe, Shawn ; Harrington, Daniel A ; Stupp, Samuel I. ; McVary, Kevin T. ; Podlasek, Carol A. / Sonic hedgehog regulation of cavernous nerve regeneration and neurite formation in aged pelvic plexus. In: Experimental Neurology. 2019 ; Vol. 312. pp. 10-19.
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N2 - Introduction: Erectile dysfunction (ED) is a significant health concern that greatly impacts quality of life, and is common in men as they age, impacting 52% of men between the ages of 40 and 70. A significant underlying cause of ED development is injury to the cavernous nerve (CN), a peripheral nerve that innervates the penis. CN injury also occurs in up to 82% of prostatectomy patients. We recently showed that Sonic hedgehog (SHH) protein delivered by peptide amphiphile (PA) nanofiber hydrogel to the CN and penis of a prostatectomy model of CN injury, is neuroprotective, accelerates CN regeneration, improves erectile function ~60%, preserves penile smooth muscle 56% and suppresses collagen deposition 30%. This regenerative potential is substantial in an adult prostatectomy model (P120). However prostatectomy patients are typically older (61.5 ± 9.6 years) and our models should mimic patient conditions more effectively when considering translation. In this study we examine regenerative potential in an aged prostatectomy model (P200–329). Methods: The caudal portion of the pelvic ganglia (MPG) and CN were dissected from adult (n = 11), and aged (n = 13) Sprague Dawley rats, and were grown in organ culture 3 days. Uninjured and 2 day CN crushed MPG/CN were exposed to Affi-Gel beads containing SHH protein, PBS (control), or 5e1 SHH inhibitor. Neurites were quantified by counting the number of growth cones normalized by tissue perimeter (mm) and immunohistochemistry for SHH, patched1 (PTCH1), smoothened (SMO), GLI1-3, and GAP43 were performed. Results: SHH treatment increased neurites 3.5-fold, in uninjured adult, and 5.7-fold in aged rats. Two days after CN crush, SHH treatment increased neurites 1.8-fold in adult rats and 2.5-fold in aged rats. SHH inhibition inhibited neurite formation in uninjured MPG/CN but not in 2 day CN crushed MPG/CN. PTCH1 and SMO (SHH receptors), and SHH transcriptional activators/repressors, GLI1-3, were abundant in aged MPG/CN with unaltered localization. ROCK1 was induced with SHH treatment. Conclusions: Reintroduction of SHH protein in an aged prostatectomy model is even more effective in promoting neurite formation/CN regeneration than in the adult. The first 48 h after CN injury are a critical window when growth factors are released, that impact later neurite formation. These studies are significant because most prostatectomy patients are not young and healthy, as with adult rats, so the aged prostatectomy model will more accurately simulate ED patient response. Understanding how neurite formation changes with age is critical for clinical translation of SHH PA to prostatectomy patients.

AB - Introduction: Erectile dysfunction (ED) is a significant health concern that greatly impacts quality of life, and is common in men as they age, impacting 52% of men between the ages of 40 and 70. A significant underlying cause of ED development is injury to the cavernous nerve (CN), a peripheral nerve that innervates the penis. CN injury also occurs in up to 82% of prostatectomy patients. We recently showed that Sonic hedgehog (SHH) protein delivered by peptide amphiphile (PA) nanofiber hydrogel to the CN and penis of a prostatectomy model of CN injury, is neuroprotective, accelerates CN regeneration, improves erectile function ~60%, preserves penile smooth muscle 56% and suppresses collagen deposition 30%. This regenerative potential is substantial in an adult prostatectomy model (P120). However prostatectomy patients are typically older (61.5 ± 9.6 years) and our models should mimic patient conditions more effectively when considering translation. In this study we examine regenerative potential in an aged prostatectomy model (P200–329). Methods: The caudal portion of the pelvic ganglia (MPG) and CN were dissected from adult (n = 11), and aged (n = 13) Sprague Dawley rats, and were grown in organ culture 3 days. Uninjured and 2 day CN crushed MPG/CN were exposed to Affi-Gel beads containing SHH protein, PBS (control), or 5e1 SHH inhibitor. Neurites were quantified by counting the number of growth cones normalized by tissue perimeter (mm) and immunohistochemistry for SHH, patched1 (PTCH1), smoothened (SMO), GLI1-3, and GAP43 were performed. Results: SHH treatment increased neurites 3.5-fold, in uninjured adult, and 5.7-fold in aged rats. Two days after CN crush, SHH treatment increased neurites 1.8-fold in adult rats and 2.5-fold in aged rats. SHH inhibition inhibited neurite formation in uninjured MPG/CN but not in 2 day CN crushed MPG/CN. PTCH1 and SMO (SHH receptors), and SHH transcriptional activators/repressors, GLI1-3, were abundant in aged MPG/CN with unaltered localization. ROCK1 was induced with SHH treatment. Conclusions: Reintroduction of SHH protein in an aged prostatectomy model is even more effective in promoting neurite formation/CN regeneration than in the adult. The first 48 h after CN injury are a critical window when growth factors are released, that impact later neurite formation. These studies are significant because most prostatectomy patients are not young and healthy, as with adult rats, so the aged prostatectomy model will more accurately simulate ED patient response. Understanding how neurite formation changes with age is critical for clinical translation of SHH PA to prostatectomy patients.

KW - Aging

KW - Cavernous nerve regeneration

KW - Neurite

KW - Prostatectomy

KW - Sonic hedgehog

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