The University of Southampton
University of Southampton Institutional Repository

Ammonium tetrathiomolybdate following ischemia/reperfusion injury: chemistry, pharmacology, and impact of a new class of sulfide donor in preclinical injury models

Ammonium tetrathiomolybdate following ischemia/reperfusion injury: chemistry, pharmacology, and impact of a new class of sulfide donor in preclinical injury models
Ammonium tetrathiomolybdate following ischemia/reperfusion injury: chemistry, pharmacology, and impact of a new class of sulfide donor in preclinical injury models
Background

Early revascularization of ischemic organs is key to improving outcomes, yet consequent reperfusion injury may be harmful. Reperfusion injury is largely attributed to excess mitochondrial production of reactive oxygen species (ROS). Sulfide inhibits mitochondria and reduces ROS production. Ammonium tetrathiomolybdate (ATTM), a copper chelator, releases sulfide in a controlled and novel manner, and may offer potential therapeutic utility.

Methods and findings

In vitro, ATTM releases sulfide in a time-, pH-, temperature-, and thiol-dependent manner. Controlled sulfide release from ATTM reduces metabolism (measured as oxygen consumption) both in vivo in awake rats and ex vivo in skeletal muscle tissue, with a superior safety profile compared to standard sulfide generators. Given intravenously at reperfusion/resuscitation to rats, ATTM significantly reduced infarct size following either myocardial or cerebral ischemia, and conferred survival benefit following severe hemorrhage. Mechanistic studies (in vitro anoxia/reoxygenation) demonstrated a mitochondrial site of action (decreased MitoSOX fluorescence), where the majority of damaging ROS is produced.

Conclusions

The inorganic thiometallate ATTM represents a new class of sulfide-releasing drugs. Our findings provide impetus for further investigation of this compound as a novel adjunct therapy for reperfusion injury.

Journal Article
1549-1277
1-24
Dyson, Alex
e288e219-cdac-4c63-85c6-9c2b6cdb194c
Dal-Pizzol, Felipe
423b2dcb-e002-475f-b507-12fb935d4b13
Sabbatini, Giovanni
9f762fd9-be26-48f4-b18b-ce2bcffd5966
Lach, Anna B.
0b637147-eecb-41a8-9a08-02cae11a65ec
Galfo, Federica
533041bf-deb8-4c21-95c1-516d74686dba
Dos Santos Cardoso, Juliano
b683eea5-d3e5-49e6-92cf-5a30f0dec2a6
Pescador Mendonça, Bruna
8b357037-81a6-4fb8-a42c-790ad8626d7d
Hargreaves, Iain
970680c3-b8b5-4ddc-83df-77dc146a7552
Bollen Pinto, Bernardo
b715bf17-7b8e-49c2-a9c6-b09431cb9394
Bromage, Daniel I.
ed17425d-58f0-438a-8691-aaa14375c438
Martin, John F.
eae432ea-e68f-4828-9e2c-5e7981e29c24
Moore, Kevin P.
f33e7ec8-2551-4959-9580-88382f2d7a35
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Singer, Mervyn
87229716-c753-44ab-a382-3f93c1c5441d
Dyson, Alex
e288e219-cdac-4c63-85c6-9c2b6cdb194c
Dal-Pizzol, Felipe
423b2dcb-e002-475f-b507-12fb935d4b13
Sabbatini, Giovanni
9f762fd9-be26-48f4-b18b-ce2bcffd5966
Lach, Anna B.
0b637147-eecb-41a8-9a08-02cae11a65ec
Galfo, Federica
533041bf-deb8-4c21-95c1-516d74686dba
Dos Santos Cardoso, Juliano
b683eea5-d3e5-49e6-92cf-5a30f0dec2a6
Pescador Mendonça, Bruna
8b357037-81a6-4fb8-a42c-790ad8626d7d
Hargreaves, Iain
970680c3-b8b5-4ddc-83df-77dc146a7552
Bollen Pinto, Bernardo
b715bf17-7b8e-49c2-a9c6-b09431cb9394
Bromage, Daniel I.
ed17425d-58f0-438a-8691-aaa14375c438
Martin, John F.
eae432ea-e68f-4828-9e2c-5e7981e29c24
Moore, Kevin P.
f33e7ec8-2551-4959-9580-88382f2d7a35
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Singer, Mervyn
87229716-c753-44ab-a382-3f93c1c5441d

Dyson, Alex, Dal-Pizzol, Felipe, Sabbatini, Giovanni, Lach, Anna B., Galfo, Federica, Dos Santos Cardoso, Juliano, Pescador Mendonça, Bruna, Hargreaves, Iain, Bollen Pinto, Bernardo, Bromage, Daniel I., Martin, John F., Moore, Kevin P., Feelisch, Martin and Singer, Mervyn (2017) Ammonium tetrathiomolybdate following ischemia/reperfusion injury: chemistry, pharmacology, and impact of a new class of sulfide donor in preclinical injury models. PLoS Medicine, 14 (7), 1-24. (doi:10.1371/journal.pmed.1002310).

Record type: Article

Abstract

Background

Early revascularization of ischemic organs is key to improving outcomes, yet consequent reperfusion injury may be harmful. Reperfusion injury is largely attributed to excess mitochondrial production of reactive oxygen species (ROS). Sulfide inhibits mitochondria and reduces ROS production. Ammonium tetrathiomolybdate (ATTM), a copper chelator, releases sulfide in a controlled and novel manner, and may offer potential therapeutic utility.

Methods and findings

In vitro, ATTM releases sulfide in a time-, pH-, temperature-, and thiol-dependent manner. Controlled sulfide release from ATTM reduces metabolism (measured as oxygen consumption) both in vivo in awake rats and ex vivo in skeletal muscle tissue, with a superior safety profile compared to standard sulfide generators. Given intravenously at reperfusion/resuscitation to rats, ATTM significantly reduced infarct size following either myocardial or cerebral ischemia, and conferred survival benefit following severe hemorrhage. Mechanistic studies (in vitro anoxia/reoxygenation) demonstrated a mitochondrial site of action (decreased MitoSOX fluorescence), where the majority of damaging ROS is produced.

Conclusions

The inorganic thiometallate ATTM represents a new class of sulfide-releasing drugs. Our findings provide impetus for further investigation of this compound as a novel adjunct therapy for reperfusion injury.

Text
file - Version of Record
Available under License Creative Commons Attribution.
Download (11MB)

More information

Accepted/In Press date: 26 April 2017
e-pub ahead of print date: 5 July 2017
Keywords: Journal Article

Identifiers

Local EPrints ID: 413357
URI: https://eprints.soton.ac.uk/id/eprint/413357
ISSN: 1549-1277
PURE UUID: cbf6bf45-bf6f-434a-8655-381903639df2
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

Catalogue record

Date deposited: 22 Aug 2017 16:31
Last modified: 10 Dec 2019 01:37

Export record

Altmetrics

Contributors

Author: Alex Dyson
Author: Felipe Dal-Pizzol
Author: Giovanni Sabbatini
Author: Anna B. Lach
Author: Federica Galfo
Author: Juliano Dos Santos Cardoso
Author: Bruna Pescador Mendonça
Author: Iain Hargreaves
Author: Bernardo Bollen Pinto
Author: Daniel I. Bromage
Author: John F. Martin
Author: Kevin P. Moore
Author: Martin Feelisch ORCID iD
Author: Mervyn Singer

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×