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Cortical Bilateral Adaptations in Rats Submitted to Focal Cerebral Ischemia: Emphasis on Glial Metabolism

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Abstract

This study was performed to evaluate the bilateral effects of focal permanent ischemia (FPI) on glial metabolism in the cerebral cortex. Two and 9 days after FPI induction, we analyze [18F]FDG metabolism by micro-PET, astrocyte morphology and reactivity by immunohistochemistry, cytokines and trophic factors by ELISA, glutamate transporters by RT-PCR, monocarboxylate transporters (MCTs) by western blot, and substrate uptake and oxidation by ex vivo slices model. The FPI was induced surgically by thermocoagulation of the blood in the pial vessels of the motor and sensorimotor cortices in adult (90 days old) male Wistar rats. Neurochemical analyses were performed separately on both ipsilateral and contralateral cortical hemispheres. In both cortical hemispheres, we observed an increase in tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and glutamate transporter 1 (GLT-1) mRNA levels; lactate oxidation; and glutamate uptake and a decrease in brain-derived neurotrophic factor (BDNF) after 2 days of FPI. Nine days after FPI, we observed an increase in TNF-α levels and a decrease in BDNF, GLT-1, and glutamate aspartate transporter (GLAST) mRNA levels in both hemispheres. Additionally, most of the unilateral alterations were found only in the ipsilateral hemisphere and persisted until 9 days post-FPI. They include diminished in vivo glucose uptake and GLAST expression, followed by increased glial fibrillary acidic protein (GFAP) gray values, astrocyte reactivity, and glutamate oxidation. Astrocytes presented signs of long-lasting reactivity, showing a radial morphology. In the intact hemisphere, there was a decrease in MCT2 levels, which did not persist. Our study shows the bilateralism of glial modifications following FPI, highlighting the role of energy metabolism adaptations on brain recovery post-ischemia.

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Acknowledgments

This work was supported by the Science Without Borders Program (88881.030387/2013-1), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) e Instituto Nacional de Ciência e Tecnologia para Excitotoxicidade e Neuroproteção (573577/2008-5).

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  1. Postgraduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600 – Anexo Santa Cecília, Porto Alegre, RS, 90035-003, Brazil

    Yasmine Nonose, Pedro E. Gewehr, Roberto F. Almeida, Jussemara S. da Silva, Bruna Bellaver, Leo A. M. Martins, Eduardo R. Zimmer, André Quincozes-Santos, Diogo O. de Souza & Adriano M. de Assis

  2. Brain Institute of Rio Grande do Sul, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS, 90619-900, Brazil

    Eduardo R. Zimmer, Samuel Greggio, Gianina T. Venturin & Jaderson C. Da Costa

  3. Department of Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, 90035-003, Brazil

    André Quincozes-Santos & Diogo O. de Souza

  4. Department of Physiology, University of Lausanne, 1005, Lausanne, Switzerland

    Luc Pellerin

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Correspondence to Adriano M. de Assis.

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All animal experiments were performed in accordance with the National Institutes of Health “Guide for the Care and Use of Laboratory Animals” (NIH publication no. 80-23, revised 1996) and were approved by the Federal University of Rio Grande do Sul Animal Care and Use Committee (process number 26674).

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Supplementary Fig. 1

All brain regions analyzed assessed by microPET. (A) Hippocampus. (B) Amygdala. (C) Caudate Putamen. (D) Olfatory. (E) Tallamus. (F) Hypothalamus. (G) Superior Colliculus. (H) Inferior Colliculus. (I) Midbrain. (J) Ventral Tegmental Area. (K) CB Gray. (L) CB White. The results are expressed in SUV values of [18F]FDG uptake and all data are expressed as the means + S.E.M * represents P < 0.05 (one-way ANOVA). (n = 6 per group). (PDF 695 kb)

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Nonose, Y., Gewehr, P.E., Almeida, R.F. et al. Cortical Bilateral Adaptations in Rats Submitted to Focal Cerebral Ischemia: Emphasis on Glial Metabolism. Mol Neurobiol 55, 2025–2041 (2018). https://doi.org/10.1007/s12035-017-0458-x

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