Lack of minocycline efficiency in genetic models of Huntington's disease.
According to the recent controversy regarding the effects of minocycline in the R6/2 transgenic model of Huntington's disease (HD), this tetracycline has been re-evaluated in another model, the N171-82Q strain. Ten miligrams per kilogram minocycline was given daily from the age of 2 mo, corresponding to an early symptomatic stage. We did not observe improvement in survival, weight loss, or motor function in treated transgenic mice. In addition, minocycline failed to mitigate the ventricle enlargement as well as the striatal and cortical atrophies induced by the transgene. Using high-performance liquid chromatography, it was observed that minocycline was similarly present in the plasma and the brain of both wild-type and N171-82Q mice following 14 daily injections. Using Western blot, we show that the increased expression of procaspase-1 induced by the transgene in the cortex was significantly reduced by the antibiotic. Combining together these data support that despite minocycline crosses blood-brain barrier in N171-82Q mice and displays an expected effect on procaspase-1 expression, it does not provide protection in this HD model. These in vivo results are in accordance with in vitro data, since minocycline failed to protect against mutated Huntingtin in an inducible PC12-clone expressing exon1 of mutated Huntingtin103Q. Altogether, the present data does not support minocycline as a beneficial drug for HD.
Mievis
Stéphane
S
IRIBHM, Brussels, Belgium.
Levivier
Marc
M
Communi
David
D
Vassart
Gilbert
G
Brotchi
Jacques
J
Ledent
Catherine
C
Blum
David
D
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism; D020170:Caspase 1 / Q000096:biosynthesis; D002460:Cell Line; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D008911:Minocycline / Q000494:pharmacology / Q000627:therapeutic use*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats
D000900:Anti-Bacterial Agents; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D020170:Caspase 1; D008911:Minocycline