title: Exendin-4 Reverses Biochemical and Functional Alterations in the Blood-Brain and Blood-CSF Barriers in Diabetic Rats.
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.
authors.affiliation: Biochemistry Department, Basic Sciences Institute of Health, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Caroline
authors.initials: C
authors.lastname: Zanotto
authors.affiliation: Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Fabrício
authors.initials: F
authors.lastname: Simão
authors.affiliation: Biochemistry Department, Basic Sciences Institute of Health, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Manuela Sangalli
authors.initials: MS
authors.lastname: Gasparin
authors.affiliation: Biochemistry Department, Basic Sciences Institute of Health, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Regina
authors.initials: R
authors.lastname: Biasibetti
authors.affiliation: Biochemistry Department, Basic Sciences Institute of Health, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Lucas Silva
authors.initials: LS
authors.lastname: Tortorelli
authors.affiliation: Biochemistry Department, Basic Sciences Institute of Health, Federal University of Rio Grande do Sul, Porto Alegre, Brazil. patricianardin@gmail.com.
authors.forename: Patrícia
authors.identifier: 0000-0003-0719-9369
authors.initials: P
authors.lastname: Nardin
authors.affiliation: Biochemistry Department, Basic Sciences Institute of Health, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Carlos-Alberto
authors.initials: CA
authors.lastname: Gonçalves
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000134:cerebrospinal fluid / Q000378:metabolism*; D000077270:Exenatide; D008297:Male; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology*
chemical_list: C496032:Aqp4 protein, rat; D051401:Aquaporin 4; D010455:Peptides; D014688:Venoms; D000077270:Exenatide
keywords: Blood–brain barrier; Blood–cerebrospinal fluid barrier; Cognitive impairment; Diabetes mellitus; GLP-1 agonist