title: Chronic depletion of gonadal testosterone leads to blood-brain barrier dysfunction and inflammation in male mice.
abstract: A dysfunction in the blood-brain barrier (BBB) is associated with many neurological and metabolic disorders. Although sex steroid hormones have been shown to impact vascular tone, endothelial function, oxidative stress, and inflammatory responses, there are still no data on the role of testosterone in the regulation of BBB structure and function. In this context, we investigated the effects of gonadal testosterone depletion on the integrity of capillary BBB and the surrounding parenchyma in male mice. Our results show increased BBB permeability for different tracers and endogenous immunoglobulins in chronically testosterone-depleted male mice. These results were associated with disorganization of tight junction structures shown by electron tomography and a lower amount of tight junction proteins such as claudin-5 and ZO-1. BBB leakage was also accompanied by activation of astrocytes and microglia, and up-regulation of inflammatory molecules such as inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), interleukin 1 beta (IL-1β), and tumor necrosis factor (TNF). Supplementation of castrated male mice with testosterone restored BBB selective permeability, tight junction integrity, and almost completely abrogated the inflammatory features. The present demonstration that testosterone transiently impacts cerebrovascular physiology in adult male mice should help gain new insights into neurological and metabolic diseases linked to hypogonadism in men of all ages.
authors.affiliation: Sorbonne Universités, CNRS, Neurosciences Paris Seine-Institut de Biologie Paris Seine (NPS-IBPS), Paris, France.
authors.forename: Afnan
authors.initials: A
authors.lastname: Atallah
authors.affiliation: Sorbonne Universités, CNRS, Neurosciences Paris Seine-Institut de Biologie Paris Seine (NPS-IBPS), Paris, France.
authors.forename: Sakina
authors.initials: S
authors.lastname: Mhaouty-Kodja
authors.affiliation: Sorbonne Universités, CNRS, Neurosciences Paris Seine-Institut de Biologie Paris Seine (NPS-IBPS), Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Grange-Messent
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology* / Q000648:ultrastructure; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D002369:Castration; D062507:Claudin-5 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D008297:Male; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D013737:Testis / Q000378:metabolism* / Q000503:physiopathology; D013739:Testosterone / Q000008:administration & dosage / Q000097:blood / Q000172:deficiency* / Q000494:pharmacology; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D015854:Up-Regulation; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D062507:Claudin-5; C491511:Cldn5 protein, mouse; D053583:Interleukin-1beta; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; D013739:Testosterone; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2
keywords: Blood–brain barrier; inflammation; mouse; testosterone; tight junction