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Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of Huntington's disease.

Rose C, Menzies FM, Renna M, Acevedo-Arozena A, Corrochano S, Sadiq O, Brown SD, Rubinsztein DC - Hum. Mol. Genet. (2010)

Bottom Line: This screen suggested that rilmenidine, a well tolerated, safe, centrally acting anti-hypertensive drug, could induce autophagy in cell culture via a pathway that was independent of the mammalian target of rapamycin.Rilmenidine administration attenuated the signs of disease in a HD mouse model and reduced levels of the mutant huntingtin fragment.As rilmenidine has a long safety record and is designed for chronic use, our data suggests that it should be considered for the treatment of HD and related conditions.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.

ABSTRACT
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a polyglutamine expansion in huntingtin. There are no treatments that are known to slow the neurodegeneration caused by this mutation. Mutant huntingtin causes disease via a toxic gain-of-function mechanism and has the propensity to aggregate and form intraneuronal inclusions. One therapeutic approach for HD is to enhance the degradation of the mutant protein. We have shown that this can be achieved by upregulating autophagy, using the drug rapamycin. In order to find safer ways of inducing autophagy for clinical purposes, we previously screened United States Food and Drug Administration-approved drugs for their autophagy-stimulating potential. This screen suggested that rilmenidine, a well tolerated, safe, centrally acting anti-hypertensive drug, could induce autophagy in cell culture via a pathway that was independent of the mammalian target of rapamycin. Here we have shown that rilmenidine induces autophagy in mice and in primary neuronal culture. Rilmenidine administration attenuated the signs of disease in a HD mouse model and reduced levels of the mutant huntingtin fragment. As rilmenidine has a long safety record and is designed for chronic use, our data suggests that it should be considered for the treatment of HD and related conditions.

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Related in: MedlinePlus

Rilmenidine treatment decreases soluble huntingtin levels, but not aggregates. (A and B) Quantification of soluble huntingtin levels was carried out by western blotting with IRDye conjugated secondary antibodies and measurement of fluorescence intensity of the bands corresponding to mutant huntingtin and actin, as a loading control. Representative lanes from the western blot are shown in (A) and quantification is shown in (B) (*P < 0.05 by t-test, n = 7 for control, placebo-treated mice and n = 6 for rilmenidine-treated mice, error bars represent SEM). (C) Aggregate number was counted in the motor cortex of control, placebo-treated and rilmenidine-treated 171-82Q transgenic mice. Aggregates were counted on three sections from three mice in each group (P = n.s. by t-test).
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DDQ093F6: Rilmenidine treatment decreases soluble huntingtin levels, but not aggregates. (A and B) Quantification of soluble huntingtin levels was carried out by western blotting with IRDye conjugated secondary antibodies and measurement of fluorescence intensity of the bands corresponding to mutant huntingtin and actin, as a loading control. Representative lanes from the western blot are shown in (A) and quantification is shown in (B) (*P < 0.05 by t-test, n = 7 for control, placebo-treated mice and n = 6 for rilmenidine-treated mice, error bars represent SEM). (C) Aggregate number was counted in the motor cortex of control, placebo-treated and rilmenidine-treated 171-82Q transgenic mice. Aggregates were counted on three sections from three mice in each group (P = n.s. by t-test).

Mentions: In order to investigate the effect of rilmenidine treatment on levels of mutant huntingtin in the brains of transgenic, mice we measured the levels of the soluble htt-exon1 fragment using quantitative western blotting methods. A small change in soluble huntingtin levels was observed after a 6-week period of drug treatment (Fig. 6A and B). This is compatible with a biologically significant enhancement of transgene clearance, since this transgene has a long half-life (11).


Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of Huntington's disease.

Rose C, Menzies FM, Renna M, Acevedo-Arozena A, Corrochano S, Sadiq O, Brown SD, Rubinsztein DC - Hum. Mol. Genet. (2010)

Rilmenidine treatment decreases soluble huntingtin levels, but not aggregates. (A and B) Quantification of soluble huntingtin levels was carried out by western blotting with IRDye conjugated secondary antibodies and measurement of fluorescence intensity of the bands corresponding to mutant huntingtin and actin, as a loading control. Representative lanes from the western blot are shown in (A) and quantification is shown in (B) (*P < 0.05 by t-test, n = 7 for control, placebo-treated mice and n = 6 for rilmenidine-treated mice, error bars represent SEM). (C) Aggregate number was counted in the motor cortex of control, placebo-treated and rilmenidine-treated 171-82Q transgenic mice. Aggregates were counted on three sections from three mice in each group (P = n.s. by t-test).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2865373&req=5

DDQ093F6: Rilmenidine treatment decreases soluble huntingtin levels, but not aggregates. (A and B) Quantification of soluble huntingtin levels was carried out by western blotting with IRDye conjugated secondary antibodies and measurement of fluorescence intensity of the bands corresponding to mutant huntingtin and actin, as a loading control. Representative lanes from the western blot are shown in (A) and quantification is shown in (B) (*P < 0.05 by t-test, n = 7 for control, placebo-treated mice and n = 6 for rilmenidine-treated mice, error bars represent SEM). (C) Aggregate number was counted in the motor cortex of control, placebo-treated and rilmenidine-treated 171-82Q transgenic mice. Aggregates were counted on three sections from three mice in each group (P = n.s. by t-test).
Mentions: In order to investigate the effect of rilmenidine treatment on levels of mutant huntingtin in the brains of transgenic, mice we measured the levels of the soluble htt-exon1 fragment using quantitative western blotting methods. A small change in soluble huntingtin levels was observed after a 6-week period of drug treatment (Fig. 6A and B). This is compatible with a biologically significant enhancement of transgene clearance, since this transgene has a long half-life (11).

Bottom Line: This screen suggested that rilmenidine, a well tolerated, safe, centrally acting anti-hypertensive drug, could induce autophagy in cell culture via a pathway that was independent of the mammalian target of rapamycin.Rilmenidine administration attenuated the signs of disease in a HD mouse model and reduced levels of the mutant huntingtin fragment.As rilmenidine has a long safety record and is designed for chronic use, our data suggests that it should be considered for the treatment of HD and related conditions.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.

ABSTRACT
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a polyglutamine expansion in huntingtin. There are no treatments that are known to slow the neurodegeneration caused by this mutation. Mutant huntingtin causes disease via a toxic gain-of-function mechanism and has the propensity to aggregate and form intraneuronal inclusions. One therapeutic approach for HD is to enhance the degradation of the mutant protein. We have shown that this can be achieved by upregulating autophagy, using the drug rapamycin. In order to find safer ways of inducing autophagy for clinical purposes, we previously screened United States Food and Drug Administration-approved drugs for their autophagy-stimulating potential. This screen suggested that rilmenidine, a well tolerated, safe, centrally acting anti-hypertensive drug, could induce autophagy in cell culture via a pathway that was independent of the mammalian target of rapamycin. Here we have shown that rilmenidine induces autophagy in mice and in primary neuronal culture. Rilmenidine administration attenuated the signs of disease in a HD mouse model and reduced levels of the mutant huntingtin fragment. As rilmenidine has a long safety record and is designed for chronic use, our data suggests that it should be considered for the treatment of HD and related conditions.

Show MeSH
Related in: MedlinePlus