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Imeglimin Is Neuroprotective Against Ischemic Brain Injury in Rats—a Study Evaluating Neuroinflammation and Mitochondrial Functions

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Abstract

Imeglimin is a novel oral antidiabetic drug modulating mitochondrial functions. However, neuroprotective effects of this drug have not been investigated. The aim of this study was to investigate effects of imeglimin against ischemia-induced brain damage and neurological deficits and whether it acted via inhibition of mitochondrial permeability transition pore (mPTP) and suppression of microglial activation. Ischemia in rats was induced by permanent middle cerebral artery occlusion (pMCAO) for 48 h. Imeglimin (135 μg/kg/day) was injected intraperitoneally immediately after pMCAO and repeated after 24 h. Immunohistochemical staining was used to evaluate total numbers of neurons, astrocytes, and microglia as well as interleukin-10 (IL-10) producing cells in brain slices. Respiration of isolated brain mitochondria was assessed using high-resolution respirometry. Assessment of ionomycin-induced mPTP opening in intact cultured primary rat neuronal, astrocytic, and microglial cells was performed using fluorescence microscopy. Treatment with imeglimin significantly decreased infarct size, brain edema, and neurological deficits after pMCAO. Moreover, imeglimin protected against pMCAO-induced neuronal loss as well as microglial proliferation and activation, and increased the number of astrocytes and the number of cells producing anti-inflammatory cytokine IL-10 in the ischemic hemisphere. Imeglimin in vitro acutely prevented mPTP opening in cultured neurons and astrocytes but not in microglial cells; however, treatment with imeglimin did not prevent ischemia-induced mitochondrial respiratory dysfunction after pMCAO. This study demonstrates that post-stroke treatment with imeglimin exerts neuroprotective effects by reducing infarct size and neuronal loss possibly via the resolution of neuroinflammation and partly via inhibition of mPTP opening in neurons and astrocytes.

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Abbreviations

Ara-c:

β-d

Arabinofuranoside

BSA:

Bovine serum albumin

Cat:

Carboxy-atractiloside

CCCP:

Carbonyl cyanide m-chlorophenylhydrazone

CGC:

Cerebellar granule cell

CsA:

Cyclosporin A

DIV:

Day in vitro

DMEM:

Dulbecco’s modified Eagle medium

DMSO:

Dimethyl sulfoxide

EGTA:

3,12-Bis(carboxymethyl)-6,9-dioxa-3,12-diazatetradecane-1,14-dioic acid

FBS:

Fetal bovine serum

GFAP:

Glial fibrillary acidic protein

HBSS:

Hank’s Balanced Salt Solution

HEPES:

4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid

Iba-1:

Ionized calcium-binding adaptor molecule 1

IL-10:

Interleukin-10

LEAK:

Proton leak-associated respiration

mPTP:

Mitochondrial permeability transition pore

NeuN:

Neuronal nuclear antigen

OCRs:

Oxygen consumption rates

PBS:

Phosphate-buffered saline

PEG300:

Polyethylene glycol 300

PFA:

Paraformaldehyde

PM:

Pyruvate, malate

pMCAO:

Permanent middle cerebral artery occlusion

PMG:

Pyruvate, malate, glutamate

ROS:

Reactive oxygen species

SEM:

Standard error of the mean

Succ:

Succinate

TTC:

2,3,5-Triphenyltetrazolium chloride

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Acknowledgements

We would like to thank Prof. Dr. Dainius Pauza and Dr. Kristina Rysevaite-Kyguoliene from Lithuanian University of Health Sciences, the Institute of Anatomy, for opportunity to use their facilities. We also wish to thank Ieva Navickaite from Lithuanian University of Health Sciences, Department of Neurology, for her help.

Availability of Data and Materials

The data that support the findings of this study are available from the corresponding author upon request.

Funding

This study has received funding from European Social Fund (project no. 09.3.3-LMT-K-712-01-0131) under grant agreement with the Research Council of Lithuania (LMTLT).

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Authors and Affiliations

  1. Department of Neurology, Medical Academy, Lithuanian University of Health Sciences, A. Mickeviciaus str. 9, LT-44307, Kaunas, Lithuania

    Gintare Zemgulyte & Daiva Rastenyte

  2. Neuroscience Institute, Medical Academy, Lithuanian University of Health Sciences, Eiveniu str. 4, LT-50162, Kaunas, Lithuania

    Danielius Umbrasas, Paulius Cizas, Silvija Jankeviciute, Katryna Pampuscenko & Vilmante Borutaite

  3. Biological research center, Lithuanian University of Health Sciences, Tilzes str. 18, LT-47181, Kaunas, Lithuania

    Ramune Grigaleviciute

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  1. Gintare Zemgulyte
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Contributions

Gintare Zemgulyte, Daiva Rastenyte, and Vilmante Borutaite designed the research. Gintare Zemgulyte, Danielius Umbrasas, Ramune Grigaleviciute, Katryna Pampuscenko, Silvija Jankeviciute, and Paulius Cicas performed experiments. Gintare Zemgulyte, Danielius Umbrasas, Ramune Grigaleviciute, Katryna Pampuscenko, Silvija Jankeviciute, Paulius Cizas, Daiva Rastenyte, and Vilmante Borutaite analyzed data, wrote the first draft of the manuscript, and edited the manuscript. Daiva Rastenyte and Vilmante Borutaite supervised the design and completion of the experiments. Gintare Zemgulyte, Danielius Umbrasas, Ramune Grigaleviciute, Katryna Pampuscenko, Silvija Jankeviciute, Paulius Cizas, Daiva Rastenyte, and Vilmante Borutaite wrote and edited the final manuscript. All authors read and approved the final manuscript.

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Correspondence to Gintare Zemgulyte.

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The study was conducted according to EU Directive 2010/63/EU for animal experiments and the Republic of Lithuania law on the care, keeping, and use of experimental animals (approved by Lithuanian State Food and Veterinary Service, ethical approval no. B6 (1.9) - 855 and no. G2-79).

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Zemgulyte, G., Umbrasas, D., Cizas, P. et al. Imeglimin Is Neuroprotective Against Ischemic Brain Injury in Rats—a Study Evaluating Neuroinflammation and Mitochondrial Functions. Mol Neurobiol 59, 2977–2991 (2022). https://doi.org/10.1007/s12035-022-02765-y

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