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Exendin-4 Reverses Biochemical and Functional Alterations in the Blood–Brain and Blood–CSF Barriers in Diabetic Rats

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Abstract

Diabetes mellitus (DM) is a metabolic disorder associated with micro- and macrovascular alterations that contribute to the cognitive impairment observed in diabetic patients. Signs of breakdown of the blood–brain barrier (BBB) and the blood–cerebrospinal fluid barrier (BCSFB) have been found in patients and animal models of DM. Breakdown of the BBB and BCSFB can lead to disruptions in cerebral homeostasis and eventually neural dysfunction and degeneration. However, our understanding of the biochemistry underlying barrier protein modifications is incomplete. Herein, we evaluated changes in the levels of specific proteins in the BBB (occludin, claudin-5, ZO-1, and aquaporin-4) and BCSFB (claudin-2 and aquaporin-1) in the hippocampus of diabetic rats, and we also investigated the functional alterations in these barriers. In addition, we evaluated the ability of exendin-4 (EX-4), a glucagon-like peptide-1 agonist that can cross the BBB to reverse the functional and biochemical modifications observed in these animals. We observed a decrease in BBB proteins (except ZO-1) in diabetic rats, whereas the EX-4 treatment recovered the occludin and aquaporin-4 levels. Similarly, we observed a decrease in BCSFB proteins in diabetic rats, whereas EX-4 reversed such changes. EX-4 also reversed alterations in the permeability of the BBB and BCSFB in diabetic rats. Additionally, altered cognitive parameters in diabetic rats were improved by EX-4. These data further our understanding of the alterations in the central nervous system caused by DM, particularly changes in the proteins and permeability of the brain barriers, as well as cognitive dysfunction. Furthermore, these data suggest a role for EX-4 in therapeutic strategies for cognitive dysfunction in DM.

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Acknowledgments

This study was supported by the National Council for Scientific and Technological Development (CNPq, Brazil), Ministry of Education (MEC/CAPES, Brazi), State Foundation for Scientific Research of Rio Grande do Sul (FAPERGS), and National Institute of Science and Technology for Excitotoxicity and Neuroprotection (MCT/INCTEN).

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Authors and Affiliations

  1. Biochemistry Department, Basic Sciences Institute of Health, Federal University of Rio Grande do Sul, Porto Alegre, Brazil

    Caroline Zanotto, Manuela Sangalli Gasparin, Regina Biasibetti, Lucas Silva Tortorelli, Patrícia Nardin & Carlos-Alberto Gonçalves

  2. Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA

    Fabrício Simão

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  1. Caroline Zanotto
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  2. Fabrício Simão
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  3. Manuela Sangalli Gasparin
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  4. Regina Biasibetti
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  6. Patrícia Nardin
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  7. Carlos-Alberto Gonçalves
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Correspondence to Patrícia Nardin.

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All animal experiments were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publications no. 80–23), and all procedures were previously approved by the local Animal Care Ethical Committee (CEUA-UFRGS; project number 24076). All efforts were made to minimize animal suffering and reduce the number of animals used.

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Zanotto, C., Simão, F., Gasparin, M.S. et al. Exendin-4 Reverses Biochemical and Functional Alterations in the Blood–Brain and Blood–CSF Barriers in Diabetic Rats. Mol Neurobiol 54, 2154–2166 (2017). https://doi.org/10.1007/s12035-016-9798-1

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