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Resveratrol Activates Neuronal Autophagy Through AMPK in the Ischemic Brain

Molecular Neurobiology volume 57, pages 1055–1069 (2020)Cite this article

Abstract

During cerebral ischemia, oxygen and glucose levels decrease, producing many consequences such as the generation of reactive oxygen species, tissue injury, and the general metabolism collapse. Resveratrol triggers signaling dependent on the protein kinase activated by adenosine monophosphate (AMPK), the sensor of cellular energy metabolism that regulates autophagy, eliminates damaged mitochondria, and increases energy sources. In the present study, we investigated the participation of AMPK activation in the protective effect of resveratrol on cerebral ischemia and excitotoxicity. We found that resveratrol increased the levels of phosphorylated AMPK in the cerebral cortex of rats subjected to middle cerebral artery occlusion (MCAO) and in primary cultured neurons exposed to glutamate-induced excitotoxicity. Resveratrol (1.8 mg/Kg; i. v.; administered at the beginning of reperfusion) decreased the infarct area and increased survival of rats subjected to MCAO. In neuronal cultures, resveratrol treatment (40 μM, after excitotoxicity) reduced the production of superoxide anion, prevented the overload of intracellular Ca+2 associated to mitochondrial failure, reduced the release of the lactate dehydrogenase enzyme, and reduced death. It also promoted mitophagy (increased Beclin 1 level, favored the recruitment of LC3-II, reduced LAMP1, and reduced mitochondrial matrix protein HSP60 levels). In both models, inhibition of AMPK activation with Compound C obstructed the effect of resveratrol, showing that its protective effect depends, partially, on the activation of the AMPK/autophagy pathway.

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Acknowledgements

This work was supported by the CONACYT (grant number CB-2012-01-182266). Anayeli Narayana Pineda-Ramírez is a doctoral student from Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM) and receiver scholarship (Number 484304) from CONACYT.

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Authors and Affiliations

  1. Laboratorio de Patología Vascular Cerebral, Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez”, Ciudad de México, 14269, México

    Narayana Pineda-Ramírez, Iván Alquisiras-Burgos & Penélope Aguilera

  2. Laboratorio de Neuropatología Experimental, Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez”, Ciudad de México, 14269, México

    Alma Ortiz-Plata

  3. Unidad de Investigación Médica en Genética Humana, Hospital de Pediatría “Dr. Silvestre Frenk Freund”, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, 06720, México

    Martha-Eugenia Ruiz-Tachiquín

  4. Laboratorio de Biología Molecular y Genómica, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Guerrero, 39087, México

    Mónica Espinoza-Rojo

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  1. Narayana Pineda-Ramírez
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Highlights

• Activation of AMPK by resveratrol prevents damage in cerebral ischemia

• Excitotoxicity in neuronal cultures is reduced by resveratrol through AMPK activation

• AMPK promotes autophagy and protects neurons from excitotoxicity

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Pineda-Ramírez, N., Alquisiras-Burgos, I., Ortiz-Plata, A. et al. Resveratrol Activates Neuronal Autophagy Through AMPK in the Ischemic Brain. Mol Neurobiol 57, 1055–1069 (2020). https://doi.org/10.1007/s12035-019-01803-6

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Keywords

  • AMPK
  • Resveratrol
  • Autophagy
  • Excitotoxicity
  • MCAO