Novel pharmacological actions of trequinsin hydrochloride improve human sperm cell motility and function

British Journal of Pharmacology
Rachel C McBrinnSean G Brown

Abstract

Asthenozoospermia is a leading cause of male infertility, but development of pharmacological agents to improve sperm motility is hindered by the lack of effective screening platforms and knowledge of suitable molecular targets. We have demonstrated that a high-throughput screening (HTS) strategy and established in vitro tests can identify and characterise compounds that improve sperm motility. Here, we applied HTS to identify new compounds from a novel small molecule library that increase intracellular calcium ([Ca2+ ]i ), promote human sperm cell motility, and systematically determine the mechanism of action. A validated HTS fluorometric [Ca2+ ]i assay was used to screen an in-house library of compounds. Trequinsin hydrochloride (a PDE3 inhibitor) was selected for detailed molecular (plate reader assays, electrophysiology, and cyclic nucleotide measurement) and functional (motility and acrosome reaction) testing in sperm from healthy volunteer donors and, where possible, patients. Fluorometric assays identified trequinsin as an efficacious agonist of [Ca2+ ]i , although less potent than progesterone. Functionally, trequinsin significantly increased cell hyperactivation and penetration into viscous medium in all donor sperm sam...Continue Reading

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Citations

Jan 5, 2021·Human Reproduction·M J CampbellS J Martins da Silva
Jul 28, 2020·Molecular and Cellular Endocrinology·Rita Rahban, Serge Nef
May 1, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Battistina AsproniGérard A Pinna
Sep 7, 2021·Human Reproduction·Rita RahbanSerge Nef

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Methods Mentioned

BETA
density gradient centrifugation
flow cytometry
Assay

Key Resources (RRID) Mentioned

SCR_014240
SCR_001905
SCR_002798

Software Mentioned

CatSper
Flexstation
R pwr package
Breeze
PClamp
Intellicyt
Excel
GraphPad Prism
SoftMax Pro
Activity Base

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