Minocycline and doxycycline are not beneficial in a model of Huntington's disease.
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.
Smith
Donna L
DL
Department of Medical and Molecular Genetics, King's College London, United Kingdom.
Woodman
Benjamin
B
Mahal
Amarbirpal
A
Sathasivam
Kirupa
K
Ghazi-Noori
Shabnam
S
Lowden
Philip A S
PA
Bates
Gillian P
GP
Hockly
Emma
E
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
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