The intracellular actions of trequinsin hydrochloride promotes human sperm motility

Rachel McBrinn, Sean G. Brown, Joanna Fraser, Christopher L. R. Barratt, Sarah Martins da Silva, David W. Gray, Anthony G. Hope

Research output: Contribution to conferenceAbstract

Abstract

Background & Purpose: Male infertility is a significant global health issue, in 40% of cases asthenozoospermia is the leading cause. ICSI is the primary method of ART however; this does not defer the male infertility enigma. Human sperm cells are comprised of complex signalling systems that make motility diverse and adaptive. Identifying a molecular target in spermatozoa and utilising compounds to improve cell function is desirable. This study aims to identify compounds that increase [Ca2+]i via CatSper, a fundamental ion channel for motility. 

Experimental approach: Phase 1: Utilise High Throughput Screening (HTS) to identify compounds that are potent inducers of [Ca2+]i. Phase 2: Determine the consequence on sperm functionality through motility, cell penetration and acrosome reaction. Phase 3: Determine the mechanism(s) of action through patch-clamp electrophysiology, HPLC and microplate assays. HTS performed through Dundee Drug Discovery Unit (DDU). Phases 2 & 3 conducted on human donor and patient cell populations.

Key results: HTS identified Trequinsin Hydrochloride, a repute PDE3i. Examination of the pharmacological profile at 10µM showed potent increases in [Ca2+]i via modulation of CatSper ion channel directly and partial depolarisation of KSper. pHi did not produce alkalisation-mediated potentiation of CatSper. Cyclic nucleotide assessment showed significant increases cGMP but not cAMP. Functionally Trequinsin increased cell hyperactivation and penetration into viscous media in all donors tested and did not induce premature acrosome reaction. Of the 29 patients assessed, 90% responded significantly to trequinsin treatment with boosts in cell hyperactivation. 

Conclusion and Implications: Extensive examination of trequinsin hydrochloride has shown novel pharmacological actions that stimulate cell hyperactivation and penetration. Utilising robust screening strategies and identifying specific molecular targets could provide insight into the intracellular regulation of normal and impaired sperm and may help to establish an alternative diagnostic treatment to ICSI for patients who suffer from reduced sperm cell motility.

Conference

ConferenceFertility 2019
CountryUnited Kingdom
CityBirmingham
Period3/01/195/01/19
OtherThe 12th Joint Annual Conference of the UK Fertility Societies: The Association of Clinical Embryologists, British Fertility Society and the Society for Reproduction & Fertility
Internet address

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Sperm Motility
Spermatozoa
Acrosome Reaction
Intracytoplasmic Sperm Injections
Male Infertility
Ion Channels
Cell Movement
Asthenozoospermia
Tissue Donors
Pharmacology
Electrophysiology
Cyclic Nucleotides
Drug Discovery
trequinsin
High Pressure Liquid Chromatography
Therapeutics
Population

Cite this

McBrinn, R., Brown, S. G., Fraser, J., Barratt, C. L. R., Martins da Silva, S., Gray, D. W., & Hope, A. G. (2019). The intracellular actions of trequinsin hydrochloride promotes human sperm motility. Abstract from Fertility 2019, Birmingham, United Kingdom.
McBrinn, Rachel ; Brown, Sean G. ; Fraser, Joanna ; Barratt, Christopher L. R. ; Martins da Silva, Sarah ; Gray, David W. ; Hope, Anthony G. / The intracellular actions of trequinsin hydrochloride promotes human sperm motility. Abstract from Fertility 2019, Birmingham, United Kingdom.
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abstract = "Background & Purpose: Male infertility is a significant global health issue, in 40{\%} of cases asthenozoospermia is the leading cause. ICSI is the primary method of ART however; this does not defer the male infertility enigma. Human sperm cells are comprised of complex signalling systems that make motility diverse and adaptive. Identifying a molecular target in spermatozoa and utilising compounds to improve cell function is desirable. This study aims to identify compounds that increase [Ca2+]i via CatSper, a fundamental ion channel for motility. Experimental approach: Phase 1: Utilise High Throughput Screening (HTS) to identify compounds that are potent inducers of [Ca2+]i. Phase 2: Determine the consequence on sperm functionality through motility, cell penetration and acrosome reaction. Phase 3: Determine the mechanism(s) of action through patch-clamp electrophysiology, HPLC and microplate assays. HTS performed through Dundee Drug Discovery Unit (DDU). Phases 2 & 3 conducted on human donor and patient cell populations.Key results: HTS identified Trequinsin Hydrochloride, a repute PDE3i. Examination of the pharmacological profile at 10µM showed potent increases in [Ca2+]i via modulation of CatSper ion channel directly and partial depolarisation of KSper. pHi did not produce alkalisation-mediated potentiation of CatSper. Cyclic nucleotide assessment showed significant increases cGMP but not cAMP. Functionally Trequinsin increased cell hyperactivation and penetration into viscous media in all donors tested and did not induce premature acrosome reaction. Of the 29 patients assessed, 90{\%} responded significantly to trequinsin treatment with boosts in cell hyperactivation. Conclusion and Implications: Extensive examination of trequinsin hydrochloride has shown novel pharmacological actions that stimulate cell hyperactivation and penetration. Utilising robust screening strategies and identifying specific molecular targets could provide insight into the intracellular regulation of normal and impaired sperm and may help to establish an alternative diagnostic treatment to ICSI for patients who suffer from reduced sperm cell motility.",
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McBrinn, R, Brown, SG, Fraser, J, Barratt, CLR, Martins da Silva, S, Gray, DW & Hope, AG 2019, 'The intracellular actions of trequinsin hydrochloride promotes human sperm motility' Fertility 2019, Birmingham, United Kingdom, 3/01/19 - 5/01/19, .

The intracellular actions of trequinsin hydrochloride promotes human sperm motility. / McBrinn, Rachel; Brown, Sean G.; Fraser, Joanna; Barratt, Christopher L. R.; Martins da Silva, Sarah; Gray, David W.; Hope, Anthony G.

2019. Abstract from Fertility 2019, Birmingham, United Kingdom.

Research output: Contribution to conferenceAbstract

TY - CONF

T1 - The intracellular actions of trequinsin hydrochloride promotes human sperm motility

AU - McBrinn, Rachel

AU - Brown, Sean G.

AU - Fraser, Joanna

AU - Barratt, Christopher L. R.

AU - Martins da Silva, Sarah

AU - Gray, David W.

AU - Hope, Anthony G.

PY - 2019/1/5

Y1 - 2019/1/5

N2 - Background & Purpose: Male infertility is a significant global health issue, in 40% of cases asthenozoospermia is the leading cause. ICSI is the primary method of ART however; this does not defer the male infertility enigma. Human sperm cells are comprised of complex signalling systems that make motility diverse and adaptive. Identifying a molecular target in spermatozoa and utilising compounds to improve cell function is desirable. This study aims to identify compounds that increase [Ca2+]i via CatSper, a fundamental ion channel for motility. Experimental approach: Phase 1: Utilise High Throughput Screening (HTS) to identify compounds that are potent inducers of [Ca2+]i. Phase 2: Determine the consequence on sperm functionality through motility, cell penetration and acrosome reaction. Phase 3: Determine the mechanism(s) of action through patch-clamp electrophysiology, HPLC and microplate assays. HTS performed through Dundee Drug Discovery Unit (DDU). Phases 2 & 3 conducted on human donor and patient cell populations.Key results: HTS identified Trequinsin Hydrochloride, a repute PDE3i. Examination of the pharmacological profile at 10µM showed potent increases in [Ca2+]i via modulation of CatSper ion channel directly and partial depolarisation of KSper. pHi did not produce alkalisation-mediated potentiation of CatSper. Cyclic nucleotide assessment showed significant increases cGMP but not cAMP. Functionally Trequinsin increased cell hyperactivation and penetration into viscous media in all donors tested and did not induce premature acrosome reaction. Of the 29 patients assessed, 90% responded significantly to trequinsin treatment with boosts in cell hyperactivation. Conclusion and Implications: Extensive examination of trequinsin hydrochloride has shown novel pharmacological actions that stimulate cell hyperactivation and penetration. Utilising robust screening strategies and identifying specific molecular targets could provide insight into the intracellular regulation of normal and impaired sperm and may help to establish an alternative diagnostic treatment to ICSI for patients who suffer from reduced sperm cell motility.

AB - Background & Purpose: Male infertility is a significant global health issue, in 40% of cases asthenozoospermia is the leading cause. ICSI is the primary method of ART however; this does not defer the male infertility enigma. Human sperm cells are comprised of complex signalling systems that make motility diverse and adaptive. Identifying a molecular target in spermatozoa and utilising compounds to improve cell function is desirable. This study aims to identify compounds that increase [Ca2+]i via CatSper, a fundamental ion channel for motility. Experimental approach: Phase 1: Utilise High Throughput Screening (HTS) to identify compounds that are potent inducers of [Ca2+]i. Phase 2: Determine the consequence on sperm functionality through motility, cell penetration and acrosome reaction. Phase 3: Determine the mechanism(s) of action through patch-clamp electrophysiology, HPLC and microplate assays. HTS performed through Dundee Drug Discovery Unit (DDU). Phases 2 & 3 conducted on human donor and patient cell populations.Key results: HTS identified Trequinsin Hydrochloride, a repute PDE3i. Examination of the pharmacological profile at 10µM showed potent increases in [Ca2+]i via modulation of CatSper ion channel directly and partial depolarisation of KSper. pHi did not produce alkalisation-mediated potentiation of CatSper. Cyclic nucleotide assessment showed significant increases cGMP but not cAMP. Functionally Trequinsin increased cell hyperactivation and penetration into viscous media in all donors tested and did not induce premature acrosome reaction. Of the 29 patients assessed, 90% responded significantly to trequinsin treatment with boosts in cell hyperactivation. Conclusion and Implications: Extensive examination of trequinsin hydrochloride has shown novel pharmacological actions that stimulate cell hyperactivation and penetration. Utilising robust screening strategies and identifying specific molecular targets could provide insight into the intracellular regulation of normal and impaired sperm and may help to establish an alternative diagnostic treatment to ICSI for patients who suffer from reduced sperm cell motility.

M3 - Abstract

ER -

McBrinn R, Brown SG, Fraser J, Barratt CLR, Martins da Silva S, Gray DW et al. The intracellular actions of trequinsin hydrochloride promotes human sperm motility. 2019. Abstract from Fertility 2019, Birmingham, United Kingdom.