Substance P restores spermatogenesis in busulfan-treated mice: A new strategy for male infertility therapy

Biomed Pharmacother. 2021 Jan:133:110868. doi: 10.1016/j.biopha.2020.110868. Epub 2020 Nov 9.

Abstract

Male infertility has become an important health problem that is primarily caused by testicular dysfunction with abnormal spermatogenesis. In this study, we demonstrated that the neuropeptide, substance P (SP), is essential for spermatogonia proliferation in a seminiferous tubule culture system. In addition, SP (5 nmol/kg) treatment markedly restored spermatogenesis, improved sperm quality, and increased the number of ZBTB16+ or LIN28+ undifferentiated spermatogonia as well as STRA8+ differentiated spermatogonia in a busulfan-induced non-obstructive azoospermic mouse model. Furthermore, 100 nM SP treatment in vitro significantly stimulated the proliferation of GC-1 spg cells (a spermatogonia cell line) via activation of the Erk1/2 signaling pathway. Moreover, the sperm quality and the number of spermatogonia were significantly reduced after treatment with RP67580, a selective NK-1 receptor antagonist, suggesting that SP-NK1R signaling plays an important role in spermatogenesis. Taken together, these results suggest that SP may be a potential therapeutic agent for male infertility by accelerating the restoration of spermatogenesis.

Keywords: Endogenous spermatogonia; Male infertility; Spermatogenesis; Substance P.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Azoospermia / chemically induced
  • Azoospermia / drug therapy*
  • Azoospermia / metabolism
  • Azoospermia / physiopathology
  • Busulfan
  • Cell Line
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fertility / drug effects*
  • Fertility Agents, Male / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Neurokinin-1 / agonists
  • Receptors, Neurokinin-1 / metabolism
  • Signal Transduction
  • Spermatogenesis / drug effects*
  • Spermatogonia / drug effects*
  • Spermatogonia / metabolism
  • Substance P / pharmacology*
  • Tissue Culture Techniques

Substances

  • Fertility Agents, Male
  • Receptors, Neurokinin-1
  • Substance P
  • Extracellular Signal-Regulated MAP Kinases
  • Busulfan

Supplementary concepts

  • Azoospermia, Nonobstructive