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Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease

Abstract

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.

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Figure 1: Progression of disease in R6/2 mice is inhibited by minocycline.
Figure 2: Minocycline inhibits caspase-1 activation as well as endogenous huntingtin cleavage in R6/2 mice.
Figure 3: Activation of iNOS in human and mouse HD.
Figure 4: Minocycline inhibits caspase-1 and caspase-3 expression.
Figure 5: Caspase-1 and caspase-3 inhibition are required to delay mortality of R6/2 mice.

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Acknowledgements

The authors thank E. Friedlander for editorial assistance. This work was supported by a grant from the Hereditary Disease Foundation (to R.M.F. and J.H.J.C), the Huntington Disease Society of America (to R.M.F. and J.H.J.C), the National Institutes of Health (to R.M.F., J.H.J.C, R.J.F and S.M.H) and the Veterans Administration (R.J.F.). R.M.F. is a member of the Cure Huntington's Disease Initiative of the Hereditary Disease Foundation and of the Coalition for the Cure from the Huntington's Disease Society of America.

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Correspondence to Robert M. Friedlander.

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Chen, M., Ona, V., Li, M. et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 6, 797–801 (2000). https://doi.org/10.1038/77528

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