Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease.
Huntington disease is an autosomal dominant neurodegenerative disease with no effective treatment. Minocycline is a tetracycline derivative with proven safety. After ischemia, minocycline inhibits caspase-1 and inducible nitric oxide synthetase upregulation, and reduces infarction. As caspase-1 and nitric oxide seem to play a role in Huntington disease, we evaluated the therapeutic efficacy of minocycline in the R6/2 mouse model of Huntington disease. We report that minocycline delays disease progression, inhibits caspase-1 and caspase-3 mRNA upregulation, and decreases inducible nitric oxide synthetase activity. In addition, effective pharmacotherapy in R6/2 mice requires caspase-1 and caspase-3 inhibition. This is the first demonstration of caspase-1 and caspase-3 transcriptional regulation in a Huntington disease model.
Chen
M
M
Neuroapoptosis Laboratory, Neurosurgical Service, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Ona
V O
VO
Li
M
M
Ferrante
R J
RJ
Fink
K B
KB
Zhu
S
S
Bian
J
J
Guo
L
L
Farrell
L A
LA
Hersch
S M
SM
Hobbs
W
W
Vonsattel
J P
JP
Cha
J H
JH
Friedlander
R M
RM
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D020170:Caspase 1 / Q000096:biosynthesis*; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis*; D004195:Disease Models, Animal; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects; D005069:Evaluation Studies as Topic; D005786:Gene Expression Regulation; D006816:Huntington Disease / Q000188:drug therapy* / Q000401:mortality; D051379:Mice; D008822:Mice, Transgenic; D008911:Minocycline / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II; D014158:Transcription, Genetic
D000900:Anti-Bacterial Agents; D018696:Neuroprotective Agents; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D020170:Caspase 1; D008911:Minocycline