Differences in the profile of protection afforded by TRO40303 and mild hypothermia in models of cardiac ischemia/reperfusion injury

Hansson, Magnus; Llwyd, Osian; Morin, Didier; Paulis, Damien De; Arnoux, Thomas; Gouarné, Caroline; Koul, Sasha; Engblom, Henrik; Bordet, Thierry; Tissier, Renaud; Arheden, Haakan; Erlinge, David; Halestrap, Andrew P.; Berdeaux, Alain; Pruss, Rebecca M.; Schaller, Sophie

doi:10.1016/j.ejphar.2015.04.009

Cited by 26 publications

(21 citation statements)

References 33 publications

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“…In addition to improving histological outcomes, we demonstrated a significant improvement in behavioral functionality that was associated with improved antioxidant enzyme capacity, reduced oxidative damage, and a blunted late pro-inflammatory cytokine response in brain tissue. While we used a pharmacological approach to modify metabolism, therapeutic hypothermia is a frequently studied alternative that reduces oxidative metabolism and limits ROS production in preclinical injury models [38]. However, this approach has shown inconsistent outcome benefits in clinical studies of ischemia/reperfusion injury [39].…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective effects of ammonium tetrathiomolybdate, a slow-release sulfide donor, in a rodent model of regional stroke

Mendonça¹,

Cardoso²,

Michels³

et al. 2020

ICMx

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Background: Several therapeutic strategies to rescue the brain from ischemic injury have improved outcomes after stroke; however, there is no treatment as yet for reperfusion injury, the secondary damage caused by necessary revascularization. Recently we characterized ammonium tetrathiomolybdate (ATTM), a drug used as a copper chelator over many decades in humans, as a new class of sulfide donor that shows efficacy in preclinical injury models. We hypothesized that ATTM could confer neuroprotection in a relevant rodent model of regional stroke.Methods and results: Brain ischemia was induced by transient (90-min) middle cerebral artery occlusion (tMCAO) in anesthetized Wistar rats. To mimic a clinical scenario, ATTM (or saline) was administered intravenously just prior to reperfusion. At 24 h or 7 days post-reperfusion, rats were assessed using functional (rotarod test, spontaneous locomotor activity), histological (infarct size), and molecular (antioxidant enzyme capacity, oxidative damage, and inflammation) outcome measurements. ATTM-treated animals showed improved functional activity at both 24 h and 7-days post-reperfusion, in parallel with a significant reduction in infarct size. These effects were additionally associated with increased brain antioxidant enzyme capacity, decreased oxidative damage, and a late (7-day) effect on proinflammatory cytokine levels and nitric oxide products.Conclusion: ATTM confers significant neuroprotection that, along with its known safety profile in humans, provides encouragement for its development as a novel adjunct therapy for revascularization following stroke.

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Section: Discussionmentioning

confidence: 99%

Neuroprotective effects of ammonium tetrathiomolybdate, a slow-release sulfide donor, in a rodent model of regional stroke

Mendonça¹,

Cardoso²,

Michels³

et al. 2020

ICMx

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“…This may explain why our earlier studies with the mitochondria-targeted superoxide scavenger, MitoQ, failed to demonstrate cardioprotection in the Langendorff-perfused heart [39]. It should be noted that earlier data showing protection from I/R injury of the heart by MitoQ was obtained in a whole animal model in which rats were treated for 14 days with mitoQ in their drinking water before induction of myocardial ischemia [40].…”

Section: Discussionmentioning

confidence: 99%

Real-Time Fluorescence Measurements of ROS and [Ca2+] in Ischemic / Reperfused Rat Hearts: Detectable Increases Occur only after Mitochondrial Pore Opening and Are Attenuated by Ischemic Preconditioning

et al. 2016

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Mitochondrial permeability transition pore (mPTP) opening is critical for ischemia / reperfusion (I/R) injury and is associated with increased [Ca2+] and reactive oxygen species (ROS). Here we employ surface fluorescence to establish the temporal sequence of these events in beating perfused hearts subject to global I/R. A bespoke fluorimeter was used to synchronously monitor surface fluorescence and reflectance of Langendorff-perfused rat hearts at multiple wavelengths, with simultaneous measurements of hemodynamic function. Potential interference by motion artefacts and internal filtering was assessed and minimised. Re-oxidation of NAD(P)H and flavoproteins on reperfusion (detected using autofluorescence) was rapid (t0.5 < 15 s) and significantly slower following ischemic preconditioning (IP). This argues against superoxide production from reduced Complex 1 being a critical mediator of initial mPTP opening during early reperfusion. Furthermore, MitoPY1 (a mitochondria-targeted H2O2-sensitive fluorescent probe) and aconitase activity measurements failed to detect matrix ROS increases during early reperfusion. However, two different fluorescent cytosolic ROS probes did detect ROS increases after 2–3 min of reperfusion, which was shown to be after initiation of mPTP opening. Cyclosporin A (CsA) and IP attenuated these responses and reduced infarct size. [Ca2+]i (monitored with Indo-1) increased progressively during ischemia, but dropped rapidly within 90 s of reperfusion when total mitochondrial [Ca2+] was shown to be increased. These early changes in [Ca2+] were not attenuated by IP, but substantial [Ca2+] increases were observed after 2–3 min reperfusion and these were prevented by both IP and CsA. Our data suggest that the major increases in ROS and [Ca2+] detected later in reperfusion are secondary to mPTP opening. If earlier IP-sensitive changes occur that might trigger initial mPTP opening they are below our limit of detection. Rather, we suggest that IP may inhibit initial mPTP opening by alternative mechanisms such as prevention of hexokinase 2 dissociation from mitochondria during ischemia.

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“…Pigs with induced myocardial infarction were included from three previous studies, one mechanistic study of myocardial infarction ( n = 15) [ 18 ], one cardioprotection study ( n = 15) [ 19 ] and controls from one cardioprotection study previously used for validating the original weighted algorithm for infarct quantification ( n = 8) [ 14 ]. All three animal studies conformed to the Guide for the Care and Use of Laboratory Animals United States National Institutes of Health (NIH Publication No.85-23, revised 1996) and were approved by the Regional Ethics Committee.…”

Section: Methodsmentioning

confidence: 99%

A new automatic algorithm for quantification of myocardial infarction imaged by late gadolinium enhancement cardiovascular magnetic resonance: experimental validation and comparison to expert delineations in multi-center, multi-vendor patient data

Engblom

Tufvesson

Jablonowski

et al. 2016

Journal of Cardiovascular Magnetic Resonance

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BackgroundLate gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) using magnitude inversion recovery (IR) or phase sensitive inversion recovery (PSIR) has become clinical standard for assessment of myocardial infarction (MI). However, there is no clinical standard for quantification of MI even though multiple methods have been proposed. Simple thresholds have yielded varying results and advanced algorithms have only been validated in single center studies. Therefore, the aim of this study was to develop an automatic algorithm for MI quantification in IR and PSIR LGE images and to validate the new algorithm experimentally and compare it to expert delineations in multi-center, multi-vendor patient data.MethodsThe new automatic algorithm, EWA (Expectation Maximization, weighted intensity, a priori information), was implemented using an intensity threshold by Expectation Maximization (EM) and a weighted summation to account for partial volume effects.The EWA algorithm was validated in-vivo against triphenyltetrazolium-chloride (TTC) staining (n = 7 pigs with paired IR and PSIR images) and against ex-vivo high resolution T1-weighted images (n = 23 IR and n = 13 PSIR images). The EWA algorithm was also compared to expert delineation in 124 patients from multi-center, multi-vendor clinical trials 2–6 days following first time ST-elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention (PCI) (n = 124 IR and n = 49 PSIR images).ResultsInfarct size by the EWA algorithm in vivo in pigs showed a bias to ex-vivo TTC of −1 ± 4%LVM (R = 0.84) in IR and −2 ± 3%LVM (R = 0.92) in PSIR images and a bias to ex-vivo T1-weighted images of 0 ± 4%LVM (R = 0.94) in IR and 0 ± 5%LVM (R = 0.79) in PSIR images. In multi-center patient studies, infarct size by the EWA algorithm showed a bias to expert delineation of −2 ± 6 %LVM (R = 0.81) in IR images (n = 124) and 0 ± 5%LVM (R = 0.89) in PSIR images (n = 49).ConclusionsThe EWA algorithm was validated experimentally and in patient data with a low bias in both IR and PSIR LGE images. Thus, the use of EM and a weighted intensity as in the EWA algorithm, may serve as a clinical standard for the quantification of myocardial infarction in LGE CMR images.Clinical trial registrationCHILL-MI: NCT01379261. MITOCARE: NCT01374321.

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Differences in the profile of protection afforded by TRO40303 and mild hypothermia in models of cardiac ischemia/reperfusion injury

Cited by 26 publications

References 33 publications

Neuroprotective effects of ammonium tetrathiomolybdate, a slow-release sulfide donor, in a rodent model of regional stroke

Neuroprotective effects of ammonium tetrathiomolybdate, a slow-release sulfide donor, in a rodent model of regional stroke

Real-Time Fluorescence Measurements of ROS and [Ca2+] in Ischemic / Reperfused Rat Hearts: Detectable Increases Occur only after Mitochondrial Pore Opening and Are Attenuated by Ischemic Preconditioning

A new automatic algorithm for quantification of myocardial infarction imaged by late gadolinium enhancement cardiovascular magnetic resonance: experimental validation and comparison to expert delineations in multi-center, multi-vendor patient data

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