Hydrogen peroxide suppresses excitability of gonadotropin-releasing hormone neurons in adult mouse

Santosh Rijal; Seon Hui Jang; Dong Hyu Cho; Seong Kyu Han

doi:10.3389/fendo.2022.939699

Hydrogen peroxide suppresses excitability of gonadotropin-releasing hormone neurons in adult mouse

Front Endocrinol (Lausanne). 2022 Oct 28:13:939699. doi: 10.3389/fendo.2022.939699. eCollection 2022.

Authors

Santosh Rijal¹, Seon Hui Jang¹, Dong Hyu Cho², Seong Kyu Han¹

Affiliations

¹ Department of Oral Physiology, School of Dentistry and Institute of Oral Bioscience, Jeonbuk National University, Jeonju, South Korea.
² Department of Obstetrics and Gynecology, Jeonbuk National University Medical School, Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute for Medical Sciences, Jeonbuk National University Hospital, Jeonju, South Korea.

Abstract

It has been reported that reactive oxygen species (ROS) derived from oxygen molecule reduction can interfere with the cross-talk between the hypothalamic-pituitary-gonadal (HPG) axis and other endocrine axes, thus affecting fertility. Furthermore, ROS have been linked to GnRH receptor signaling in gonadotropes involved in gonadotropin release. There has been evidence that ROS can interfere with the HPG axis and gonadotropin release at various levels. However, the direct effect of ROS on gonadotropin-releasing hormone (GnRH) neuron remains unclear. Thus, the objective of this study was to determine the effect of hydrogen peroxide (H₂O₂), an ROS source, on GnRH neuronal excitabilities in transgenic GnRH-green fluorescent protein-tagged mice using the whole-cell patch-clamp electrophysiology. In adults, H₂O₂ at high concentrations (mM level) hyperpolarized most GnRH neurons tested, whereas low concentrations (pM to μM) caused slight depolarization. In immature GnRH neurons, H₂O₂ exposure induced excitation. The sensitivity of GnRH neurons to H₂O₂ was increased with postnatal development. The effect of H₂O₂ on adult female GnRH neurons was found to be estrous cycle-dependent. Hyperpolarization mediated by H₂O₂ persisted in the presence of tetrodotoxin, a voltage-gated Na⁺ channel blocker, and amino-acids receptor blocking cocktail containing blockers for the ionotropic glutamate receptors, glycine receptors, and GABA_A receptors, indicating that H₂O₂ could act on GnRH neurons directly. Furthermore, glibenclamide, an ATP-sensitive K⁺ (K_ATP) channel blocker, completely blocked H₂O₂-mediated hyperpolarization. Increasing endogenous H₂O₂ by inhibiting glutathione peroxidase decreased spontaneous activities of most GnRH neurons. We conclude that ROS can act as signaling molecules for regulating GnRH neuron's excitability and that adult GnRH neurons are sensitive to increased ROS concentration. Results of this study demonstrate that ROS have direct modulatory effects on the HPG axis at the hypothalamic level to regulate GnRH neuron's excitabilities.

Keywords: KATP channels; gonadotropin-releasing hormone neurons; hydrogen peroxide; hypothalamic-pituitary-gonadal axis; patch-clamp; reactive oxygen species.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / pharmacology
Animals
Female
Gonadotropin-Releasing Hormone* / metabolism
Hydrogen Peroxide* / pharmacology
Mice
Mice, Transgenic
Neurons / metabolism
Reactive Oxygen Species
Receptors, GABA-A

Substances

Gonadotropin-Releasing Hormone
Hydrogen Peroxide
Reactive Oxygen Species
Receptors, GABA-A
Adenosine Triphosphate