title: High mobility group box 1 (HMGB1): dual functions in the cochlear auditory neurons in response to stress?
abstract: High mobility group box 1 (HMGB1) is a DNA-binding protein that facilitates gene transcription and may act extracellularly as a late mediator of inflammation. The roles of HMGB1 in the pathogenesis of the spiral ganglion neurons (SGNs) of the cochlea are currently unknown. In the present study, we tested the hypothesis that early phenotypical changes in the SGNs of the amikacin-poisoned rat cochlea are mediated by HMGB1. Our results showed that a marked downregulation of HMGB1 had occurred by completion of amikacin treatment, coinciding with acute damage at the dendrite extremities of the SGNs. A few days later, during the recovery of the SGN dendrites, the protein was re-expressed and transiently accumulated within the nuclei of the SGNs. The phosphorylated form of the transcription factor c-Jun (p-c-Jun) was concomitantly detected in the nuclei of the SGNs where it often co-localized with HMGB1, while the anti-apoptotic protein BCL2 was over-expressed in the cytoplasm. In animals co-treated with amikacin and the histone deacetylase inhibitor trichostatin A, both HMGB1 and p-c-Jun were exclusively found within the cytoplasm. The initial disappearance of HMGB1 from the affected SGNs may be due to its release into the external medium, where it may have a cytokine-like function. Once re-expressed and translocated into the nucleus, HMGB1 may facilitate the transcriptional activity of p-c-Jun, which in turn may promote repair mechanisms. Our study therefore suggests that HMGB1 can positively influence the survival of SGNs following ototoxic exposure via both its extracellular and intranuclear functions.
authors.affiliation: INSERM, U1051, Institute for Neurosciences (INM), Hôpital Saint Eloi, 80 rue Augustin Fliche, 34091, Montpellier Cedex 5, France.|University of Montpellier, Montpellier, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Ladrech
authors.affiliation: INSERM, U1051, Institute for Neurosciences (INM), Hôpital Saint Eloi, 80 rue Augustin Fliche, 34091, Montpellier Cedex 5, France.|University of Montpellier, Montpellier, France.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: INSERM, U1183, Institute of Regenerative Medicine and Biotherapy (IRMB), Montpellier, France.|University of Montpellier, Montpellier, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Mathieu
authors.affiliation: INSERM, U1051, Institute for Neurosciences (INM), Hôpital Saint Eloi, 80 rue Augustin Fliche, 34091, Montpellier Cedex 5, France.|University of Montpellier, Montpellier, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Puel
authors.affiliation: INSERM, U1051, Institute for Neurosciences (INM), Hôpital Saint Eloi, 80 rue Augustin Fliche, 34091, Montpellier Cedex 5, France. marc.lenoir@inserm.fr.|University of Montpellier, Montpellier, France. marc.lenoir@inserm.fr.
authors.forename: Marc
authors.initials: M
authors.lastname: Lenoir
mesh_terms: D000583:Amikacin / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D024243:HMGB1 Protein / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013136:Spiral Ganglion / Q000166:cytology*; D013312:Stress, Physiological; D013329:Structure-Activity Relationship
chemical_list: D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D006877:Hydroxamic Acids; C012589:trichostatin A; D000583:Amikacin
keywords: BCL2; Excitotoxicity; Gamma-H2ax; Ototoxicity; TSA; c-Jun