title: Minocycline and doxycycline are not beneficial in a model of Huntington's disease.
abstract: Huntington's Disease (HD) is an inherited neurological disorder causing movement impairment, personality changes, dementia, and premature death, for which there is currently no effective therapy. The modified tetracycline antibiotic, minocycline, has been reported to ameliorate the disease phenotype in the R6/2 mouse model of HD. Because the tetracyclines have also been reported to inhibit aggregation in other amyloid disorders, we have investigated their ability to inhibit huntingtin aggregation and further explored their efficacy in preclinical mouse trials. We show that tetracyclines are potent inhibitors of huntingtin aggregation in a hippocampal slice culture model of HD at an effective concentration of 30 microM. However, despite achieving tissue levels approaching this concentration by oral treatment of R6/2 mice with minocycline, we observed no clear difference in their behavioral abnormalities, or in aggregate load postmortem. In the light of these new data, we would advise that caution be exercised in proceeding into human clinical trials of minocycline.
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, United Kingdom.
authors.forename: Donna L
authors.initials: DL
authors.lastname: Smith
authors.forename: Benjamin
authors.initials: B
authors.lastname: Woodman
authors.forename: Amarbirpal
authors.initials: A
authors.lastname: Mahal
authors.forename: Kirupa
authors.initials: K
authors.lastname: Sathasivam
authors.forename: Shabnam
authors.initials: S
authors.lastname: Ghazi-Noori
authors.forename: Philip A S
authors.initials: PA
authors.lastname: Lowden
authors.forename: Gillian P
authors.initials: GP
authors.lastname: Bates
authors.forename: Emma
authors.initials: E
authors.lastname: Hockly
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D004318:Doxycycline / Q000627:therapeutic use*; D005260:Female; D005838:Genotype; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006943:Hyperglycemia / Q000097:blood; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008911:Minocycline / Q000627:therapeutic use*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009924:Organ Culture Techniques; D010455:Peptides / Q000378:metabolism; D010641:Phenotype; D004856:Postural Balance / Q000187:drug effects; D013752:Tetracycline / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine; D013752:Tetracycline; D008911:Minocycline; D004318:Doxycycline