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Lactate Protects Microglia and Neurons from Oxygen–Glucose Deprivation/Reoxygenation

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Abstract

Lactate has received attention as a potential therapeutic intervention for brain diseases, particularly those including energy deficit, exacerbated inflammation, and disrupted redox status, such as cerebral ischemia. However, lactate roles in metabolic or signaling pathways in neural cells remain elusive in the hypoxic and ischemic contexts. Here, we tested the effects of lactate on the survival of a microglial (BV-2) and a neuronal (SH-SY5Y) cell lines during oxygen and glucose deprivation (OGD) or OGD followed by reoxygenation (OGD/R). Lactate signaling was studied by using 3,5-DHBA, an exogenous agonist of lactate receptor GPR81. Inhibition of lactate dehydrogenase (LDH) or monocarboxylate transporters (MCT), using oxamate or 4-CIN, respectively, was performed to evaluate the impact of lactate metabolization and transport on cell viability. The OGD lasted 6 h and the reoxygenation lasted 24 h following OGD (OGD/R). Cell viability, extracellular lactate concentrations, microglial intracellular pH and TNF-ɑ release, and neurite elongation were evaluated. Lactate or 3,5-DHBA treatment during OGD increased microglial survival during reoxygenation. Inhibition of lactate metabolism and transport impaired microglial and neuronal viability. OGD led to intracellular acidification in BV-2 cells, and reoxygenation increased the release of TNF-ɑ, which was reverted by lactate and 3,5-DHBA treatment. Our results suggest that lactate plays a dual role in OGD, acting as a metabolic and a signaling molecule in BV-2 and SH-SY5Y cells. Lactate metabolism and transport are vital for cell survival during OGD. Moreover, lactate treatment and GPR81 activation during OGD promote long-term adaptations that potentially protect cells against secondary cell death during reoxygenation.

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Data Availability

Data are available upon reasonable request.

Abbreviations

3,5-DHBA:

3,5-Dihydroxybenzoic acid

4-CIN:

ɑ-Cyano-4-hydroxycinnamic acid

ANLS:

Astrocyte-neuron lactate shuttle

ATP:

Adenosine triphosphate

BCECF-AM:

Acetoxymethyl ester of 2′,7′-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein

cAMP:

Cyclic adenosine monophosphate

CD206:

Cluster of differentiation 206, mannose receptor

CNS:

Central nervous system

DAPI:

4′,6-Diamidino-2-phenylindole

DMEM:

Dulbecco’s Modified Eagle Medium

ELISA:

Enzyme-linked immunosorbent assay

FBS:

Fetal bovine serum

GPR81:

G protein-coupled-receptor 81

HCAR1:

Hydroxy-carboxylic acid receptor 1

HCl:

Hydrochloric acid

HEPES:

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

HIF-1α:

Hypoxia inducible factor-1, subunit alpha

OGD:

Oxygen and glucose deprivation

OGD/R:

Oxygen and glucose deprivation-reoxygenation

MCT:

Monocarboxylate transporter

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NAD+ :

Nicotinamide adenine dinucleotide, oxidized form

NADH:

Nicotinamide adenine dinucleotide, reduced form

NEFL:

Neurofilament light polypeptide

NF-κB:

Nuclear factor kappa B

NLRP3:

Nod-like receptor protein 3

pHi:

Intracellular potential of hydrogen

P/S:

Penicillin/streptomycin

PBS:

Phosphate-buffer saline

PKA:

Protein kinase A

RA:

Retinoic acid

RT:

Room temperature

TNF-α:

Tumor necrosis factor-alpha

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Acknowledgements

We want to express our gratitude to Dr. Amanda Thomaz from the Division of Biomedical and Life Sciences, Lancaster University, and also to the PhD student, Janaína Zang from the Federal University of Rio Grande do Sul (UFRGS) for their unwavering support in the immunofluorescence experiments.

Funding

This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), FIOCRUZ Institutional Internationalization Program (CAPES/PrInt-Fiocruz), UFRGS Institutional Internationalization Program (CAPES/PrInt-UFRGS), and Erasmus+ Funding Programme.

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  1. Victorio Bambini-Junior and Luciano Stürmer de Fraga have contributed equally to this work.

Authors and Affiliations

  1. Graduate Program in Physiology, Institute of Basic Health Sciences (ICBS), Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, 90050-003, Brazil

    Isadora D’Ávila Tassinari, Ana Helena Paz & Luciano Stürmer de Fraga

  2. Graduate Program in Biosciences, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, 90050-170, Brazil

    Fernanda da Silva Rodrigues & Renata Padilha Guedes

  3. Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, 21040-360, Brazil

    Daniella Arêas Mendes-da-Cruz

  4. Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YW, UK

    Isadora D’Ávila Tassinari, Fernanda da Silva Rodrigues, Daniella Arêas Mendes-da-Cruz & Victorio Bambini-Junior

  5. School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, PR1 2HE, UK

    Craig Bertram

Authors
  1. Isadora D’Ávila Tassinari
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  2. Fernanda da Silva Rodrigues
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  3. Craig Bertram
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  4. Daniella Arêas Mendes-da-Cruz
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  5. Renata Padilha Guedes
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  6. Ana Helena Paz
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  7. Victorio Bambini-Junior
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  8. Luciano Stürmer de Fraga
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Contributions

Conceived and designed the experiments: IDT, DAMC, RPG, AHP, VBJ, and LSF. Performed the experiments: IDT, and FSR. Analyzed the data: IDT, FSR, VBJ, and LSF. Data interpretation: IDT, DAMC, RPG, AHP, and LSF. Wrote the first draft of the manuscript: IDT, and LSF. Revised critically the manuscript: CB, DAMC, RPG, and AHP. Grammar review: CB. All authors reviewed the final version of the manuscript.

Corresponding author

Correspondence to Luciano Stürmer de Fraga.

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Institutional ethical approval was not required, as the present study used only cell lines, and live animals were not used in the experiments.

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Tassinari, I.D., Rodrigues, F.d., Bertram, C. et al. Lactate Protects Microglia and Neurons from Oxygen–Glucose Deprivation/Reoxygenation. Neurochem Res (2024). https://doi.org/10.1007/s11064-024-04135-7

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  • DOI: https://doi.org/10.1007/s11064-024-04135-7

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