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Therapeutic potential of a single-dose melatonin in the attenuation of cardiac ischemia/reperfusion injury in prediabetic obese rats

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Abstract

Although acute melatonin treatment effectively reduces cardiac ischemia/reperfusion (I/R) injury in lean rats by modulating melatonin receptor 2 (MT2), there is no information regarding the temporal effects of melatonin administration during cardiac I/R injury in prediabetic obese rats. Prediabetic obese rats induced by chronic consumption of a high-fat diet (HFD) were used. The rats underwent a cardiac I/R surgical procedure (30-min of ischemia, followed by 120-min of reperfusion) and were randomly assigned to receive either vehicle or melatonin treatment. In the melatonin group, rats were divided into 3 different subgroups: (1) pretreatment, (2) treatment during ischemic period, (3) treatment at the reperfusion onset. In the pretreatment subgroup either a nonspecific MT blocker (Luzindole) or specific MT2 blocker (4-PPDOT) was also given to the rats prior to melatonin treatment. Pretreatment with melatonin (10 mg/kg) effectively reduced cardiac I/R injury by reducing infarct size, arrhythmia, and LV dysfunction. Reduction in impaired mitochondrial function, mitochondrial dynamic balance, oxidative stress, defective autophagy, and apoptosis were observed in rats pretreated with melatonin. Unfortunately, the cardioprotective benefits were not observed when 10-mg/kg of melatonin was acutely administered to the rats after cardiac ischemia. Thus, we increased the dose of melatonin to 20 mg/kg, and it was administered to the rats during ischemia or at the onset of reperfusion. The results showed that 20-mg/kg of melatonin effectively reduced cardiac I/R injury to a similar extent to the 10-mg/kg pretreatment regimen. The MT2 blocker inhibited the protective effects of melatonin. Acute melatonin treatment during cardiac I/R injury exerted protective effects in prediabetic obese rats. However, a higher dose of melatonin is required when given after the onset of cardiac ischemia. These effects of melatonin were mainly mediated through activation of MT2.

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Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Code availability

Not applicable.

Abbreviations

LV:

Left ventricular

Cardiac I/R injury:

Cardiac ischemia/reperfusion injury

HFD:

High-fat diet

Mel:

Melatonin

ND:

Normal diet

MT:

Melatonin receptor

Drp1:

Dynamin related protein 1

Opa1:

Optic atrophy 1

Mfn1:

Mitofusin 1

Mfn2:

Mitofusin 2

NSS:

Normal saline solution

Luz:

Luzindole

Dot:

4-PPDOT

HF-PMel:

Prediabetic obese rats pretreatment with melatonin

HF-IMel:

Prediabetic obese rats treated with melatonin during myocardial ischemia

HF-RMel:

Prediabetic obese rats treated with melatonin at onset of reperfusion

HF-MelLuz:

Prediabetic obese rats treated with melatonin and Luzindole

HF-MelDot:

Prediabetic obese rats treated with melatonin and 4-PPDOT

iv:

Intravenous

ECG:

Electrocardiogram

TTC:

2,3,5-Triphenyltetrazolium chloride

LAD:

Left anteriror descending coronary artery

HR:

Heart rate

LVEF:

Left ventricular ejection fraction

LVESP:

Left ventricular end-systolic pressure

LVEDP:

Left ventricular end-diastolic pressure

AAR:

Area at risk

MDA:

Malondialdehyde

ROS:

Reactive oxygen species

a.u.:

Arbitrary unit

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Funding

This work was supported by the NSTDA Research Chair grant from the National Science and Technology Development Agency Thailand (NC); the Senior Research Scholar grant from the National Research Council of Thailand (SCC); the Thailand Research Fund Royal Golden Jubilee PhD Program PHD/0107/2560 (KS and NC); the National Research Council of Thailand (N41A640112 to NA); and the Chiang Mai University Center of Excellence Award (NC).

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Authors and Affiliations

  1. Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand

    Kodchanan Singhanat, Nattayaporn Apaijai, Natticha Sumneang, Chayodom Maneechote, Busarin Arunsak, Titikorn Chunchai, Siriporn C. Chattipakorn & Nipon Chattipakorn

  2. Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand

    Kodchanan Singhanat, Nattayaporn Apaijai, Natticha Sumneang, Chayodom Maneechote, Busarin Arunsak, Titikorn Chunchai, Siriporn C. Chattipakorn & Nipon Chattipakorn

  3. Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand

    Kodchanan Singhanat, Nattayaporn Apaijai, Natticha Sumneang & Nipon Chattipakorn

  4. Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, 50200, Thailand

    Siriporn C. Chattipakorn

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  1. Kodchanan Singhanat
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  2. Nattayaporn Apaijai
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  7. Siriporn C. Chattipakorn
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  8. Nipon Chattipakorn
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Contributions

SCC and NC: conception; KS, NA, NS, CM, BA, and TJ: data collection; KS, NA, SCC, and NC: data analysis; KS and NA: drafting of the manuscript; SCC and NC: revision of the manuscript and final approval.

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Correspondence to Nipon Chattipakorn.

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All animal experiments followed the NIH guidelines and were authorized by Chiang Mai University’s Institutional Animal Care and Use Committee (approval no. 2563/RT-0004).

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Singhanat, K., Apaijai, N., Sumneang, N. et al. Therapeutic potential of a single-dose melatonin in the attenuation of cardiac ischemia/reperfusion injury in prediabetic obese rats. Cell. Mol. Life Sci. 79, 300 (2022). https://doi.org/10.1007/s00018-022-04330-1

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