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Role of Modulation of Hippocampal Glucose Following Pilocarpine-Induced Status Epilepticus

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Abstract

Status epilepticus (SE) is defined as continuous and self-sustaining seizures, which trigger hippocampal neurodegeneration, mitochondrial dysfunction, oxidative stress, and energy failure. During SE, the neurons become overexcited, increasing energy consumption. Glucose uptake is increased via the sodium glucose cotransporter 1 (SGLT1) in the hippocampus under epileptic conditions. In addition, modulation of glucose can prevent neuronal damage caused by SE. Here, we evaluated the effect of increased glucose availability in behavior of limbic seizures, memory dysfunction, neurodegeneration process, neuronal activity, and SGLT1 expression. Vehicle (VEH, saline 0.9%, 1 μL) or glucose (GLU; 1, 2 or 3 mM, 1 μL) were administered into hippocampus of male Wistar rats (Rattus norvegicus) before or after pilocarpine to induce SE. Behavioral analysis of seizures was performed for 90 min during SE. The memory and learning processes were analyzed by the inhibitory avoidance test. After 24 h of SE, neurodegeneration process, neuronal activity, and SGLT1 expression were evaluated in hippocampal and extrahippocampal regions. Modulation of hippocampal glucose did not protect memory dysfunction followed by SE. Our results showed that the administration of glucose after pilocarpine reduced the severity of seizures, as well as the number of limbic seizures. Similarly, glucose after SE reduced cell death and neuronal activity in hippocampus, subiculum, thalamus, amygdala, and cortical areas. Finally, glucose infusion elevated the SGLT1 expression in hippocampus. Taken together our data suggest that possibly the administration of intrahippocampal glucose protects brain in the earlier stage of epileptogenic processes via an important support of SGLT1.

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Acknowledgments

DLGG was supported by the Research Productivity Scholarship Program in Brazilian National Council for Scientific and Technological Development (CNPq). We thank CAPES-Brazil for PhD Research Fellowship to I.S.M., Y.M.O.S., A.L.D.P., M.A.C., and J.F.S.

Funding

This project was supported by FAPEAL, CNPq, and CAPES.

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Authors and Affiliations

  1. Department of Physiology, Institute of Biological Sciences and Health, Federal University of Alagoas (UFAL), Maceió, AL, Brazil

    Igor Santana de Melo, Yngrid Mickaelli Oliveira dos Santos, Amanda Larissa Dias Pacheco, Maisa Araújo Costa, Vanessa de Oliveira Silva, Jucilene Freitas-Santos, Cibelle de Melo Bastos Cavalcante, Daniel Góes Leite Gitaí, Marcelo Duzzioni, Robinson Sabino-Silva, Alexandre Urban Borbely & Olagide Wagner de Castro

  2. Bioenergetics Laboratory, Institute of Chemistry and Biotechnology, Federal University of Alagoas (UFAL), Maceió, AL, Brazil

    Reginaldo Correia Silva-Filho & Ana Catarina Rezende Leite

  3. Department of Physiology, Institute of Biomedical Sciences, Federal University of Uberlandia (UFU), Uberlândia, MG, Brazil

    Robinson Sabino-Silva

Authors
  1. Igor Santana de Melo
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Contributions

Conceptualization, I.S.M., R.S.S., and O.W.C.; methodology, I.S.M., Y.M.O.S., A.L.D.P., M.A.C., V.O.S., J.F.S., C.M.B.C., R.C.S.F, A.C.R.L., R.S.S., and O.W.C.; investigation, I.S.M., A.C.R.L., A.U.B., R.S.S., and O.W.C.; formal analysis, I.S.M., R.C.S.F, A.C.R.L., R.S.S., and O.W.C.; supervision and fund acquisition, O.W.C.; writing—review and editing, I.S.M., D.G.L.G., M.D., A.U.B., R.S.S., and O.W.C.; resources, M.D., A.U.B., R.S.S., and O.W.C.

Corresponding author

Correspondence to Olagide Wagner de Castro.

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Conflict of Interests

The authors declare that they have no conflict of interest.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Experiments were performed in accordance with the NIH guidelines for the care and use of laboratory animals, and with approval of the Federal University of Alagoas Animal Use Ethics Committee.

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Supplementary Information

Online Resource 1

Effects of increased glucose availability on status of oxidative stress levels in rat hippocampus after 24 h of intrahippocampal pilocarpine-induced SE. Modulated levels of malondialdehyde (MDA), total thiol, catalase (CAT), and superoxide dismutase (SOD) were assessed (A). Glucose-(3 mM)-treated rats showed a significant increase in MDA levels (B) and a significant decrease in total thiol (C), CAT (D) and SOD (E) levels compared with saline-treated rats. Error bars indicate the SEM. Data represent the mean ± S.E.M. of 4–6 rats. *P < 0.05, **P < 0.01, and ***P < 0.001 compared with VEH; one-way ANOVA with Dunnett’s post-hoc test. VEH, saline-treated vehicle; H-PILO, pilocarpine and saline; P+G, pilocarpine followed by glucose infusion; DZP, diazepam; SE, Status epilepticus; SEM, standard error of the mean. (PNG 1620 kb)

High resolution image (TIF 255 kb)

Online Resource 2

Glucose modulation decreases the cFOS expression in cortical and subiculum areas after intrahippocampal pilocarpine-induced SE. The nuclei were labeled with DAPI (blue, middle panels, A-H2). Fluorescent labeling strong cFOS immunoreactivity (red, left panels) in RSGr (A1), Prh (C1), Pir (E1) and DS (G1) in H-PILO rats. Merge of cFOS and DAPI are shown in right panels (A-H3). Quantitative analysis of cFOS+ neurons in H-PILO (black bars), G+P (gray, blue and red bar) and P+G (gray, blue and red bar outline) rats are shown in B4, D4, F4 and H4. Some concentrations of hippocampal glucose (1, 2 or 3 mM) before and after intrahippocampal pilocarpine attenuated the number of cFOS+ neurons in RSGr (one-way ANOVA, F (6, 22) = 3.59, P = 0.012; B4), Prh (t-test, t5 = 3.79, P = 0.013; D4), Pir (one-way ANOVA, F (6, 16) = 3.70, P = 0.017; F4) and DS (one-way ANOVA, F (6, 20) = 6.51, P = 0.0006; H4) areas. The 3 mM glucose concentration was used as a representative image. Arrows represent the brain areas. Magnification, 200x; scale bar, 50 μm. Error bars indicate the SEM. Data represent the mean ± S.E.M. of 3–6 rats. *P < 0.05, **P < 0.01 and ***P < 0.001 compared with H-PILO; one-way ANOVA with Dunnett’s post-hoc test and unpaired t-test. H-PILO, pilocarpine and saline; G+P, glucose followed by pilocarpine infusion; P+G, pilocarpine followed by glucose infusion; RSGr, retrosplenial; PRh, perirhinal; Pir, piriform; DS, subiculum; SEM, standard error of the mean. (PNG 4306 kb)

High resolution image (TIF 1274 kb)

Online Resource 3

Increased glucose supply decreases the cFOS expression in thalamic and amygdaloid areas after intrahippocampal pilocarpine-induced SE. The nuclei were labeled with DAPI (blue, middle panels). Fluorescent labeling of the hippocampus shows strong cFOS immunoreactivity (red, left panels) in LPMR (A1), CL (C1), PVP (E1) and LaDL (G1) in H-PILO rats. Merge of cFOS and DAPI shown in right panels. Quantitative analysis of cFOS+ neurons in H-PILO (black bars), G+P (gray, blue and red bar) and P+G (gray, blue and red bar outline) rats are shown in B4, D4, F4 and H4. Some concentrations of hippocampal glucose (1, 2 or 3 mM) before and after intrahippocampal pilocarpine decreased the number of cFOS+ neurons in LPMR (one-way ANOVA, F (6, 22) = 10.94, P < 0.0001; B4), CL (one-way ANOVA, F (6, 22) = 3.54, P = 0.01; D4), PVP (one-way ANOVA, F (6, 20) = 5.21, P = 0.0023; F4) and LaDL (one-way ANOVA, F (3, 9) = 9.65, P = 0.0036; H4) areas. The 3 mM glucose concentration was used as a representative image. Arrows represent the brain areas. Magnification, 200x; scale bar, 50 μm. Error bars indicate the SEM. Data represent the mean ± S.E.M. of 5–6 rats. *P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001 compared with H-PILO; one-way ANOVA with Dunnett’s post-hoc test. H-PILO, pilocarpine and saline; G+P, glucose followed by pilocarpine infusion; P+G, pilocarpine followed by glucose infusion; PVP, posterior paraventricular th ncl; CL, centrolateral th ncl; LPMR, lateral posterior th ncl; LaDL, lateral amygdaloid ncl; SEM, standard error of the mean. (PNG 4591 kb)

High resolution image (TIF 1223 kb)

Online Resource 4

Glucose supply reduces the seizures severity but does not change memory dysfunction and oxidative stress. Cell death and neuronal activity are attenuated in the hippocampus and extrahippocampal areas because of this glucose control, via elevation of sodium-glucose cotransporter translocation in hippocampus. (PNG 3670 kb)

High resolution image (TIF 1811 kb)

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de Melo, I.S., dos Santos, Y.M.O., Pacheco, A.L.D. et al. Role of Modulation of Hippocampal Glucose Following Pilocarpine-Induced Status Epilepticus. Mol Neurobiol 58, 1217–1236 (2021). https://doi.org/10.1007/s12035-020-02173-0

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