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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 improved overall performance at the wire manoeuvre task as well as the severity of tremors at certain time points in N171-82Q mice. (A) Mice were scored on their ability to perform the wire manoeuvre, score: 0, active grip with hind legs; 1, difficulty grasping with hind legs; 2, unable to lift hind legs; 3, falls within 30 s; 4, falls immediately. The percentage of animals obtaining each score is shown in the graphs, black bars represent rilmenidine-treated animals and white bars represent control, placebo-treated animals. Significant differences between treatment groups were seen at 12 weeks (P = 0.002), 14 weeks (P = 0.017), 16 weeks (P = 0.0246), 18 weeks (P = 0.0211) and 20 weeks (P=0.0056) of age (Mann–Whitney U test). No significant differences were seen pre-treatment at 4 weeks as well as at 22 weeks (P = 0.1495) of age. (B) The severity of tremors in N171-82Q mice was significantly improved by rilmenidine treatment at 16 weeks (P = 0.0403) and 18 weeks (P = 0.0293) of age, and a trend towards an improvement was also evident at the age of 12 weeks (P = 0.0583) in comparison to the control group. No significant differences were seen at 14 weeks (P = 0.1762), 20 weeks (P = 0.2987) and 22 weeks (P = 0.3367) of age. Score: 0, no tremor; 1, mild tremor; 2, severe tremor.
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DDQ093F3: Rilmenidine treatment improved overall performance at the wire manoeuvre task as well as the severity of tremors at certain time points in N171-82Q mice. (A) Mice were scored on their ability to perform the wire manoeuvre, score: 0, active grip with hind legs; 1, difficulty grasping with hind legs; 2, unable to lift hind legs; 3, falls within 30 s; 4, falls immediately. The percentage of animals obtaining each score is shown in the graphs, black bars represent rilmenidine-treated animals and white bars represent control, placebo-treated animals. Significant differences between treatment groups were seen at 12 weeks (P = 0.002), 14 weeks (P = 0.017), 16 weeks (P = 0.0246), 18 weeks (P = 0.0211) and 20 weeks (P=0.0056) of age (Mann–Whitney U test). No significant differences were seen pre-treatment at 4 weeks as well as at 22 weeks (P = 0.1495) of age. (B) The severity of tremors in N171-82Q mice was significantly improved by rilmenidine treatment at 16 weeks (P = 0.0403) and 18 weeks (P = 0.0293) of age, and a trend towards an improvement was also evident at the age of 12 weeks (P = 0.0583) in comparison to the control group. No significant differences were seen at 14 weeks (P = 0.1762), 20 weeks (P = 0.2987) and 22 weeks (P = 0.3367) of age. Score: 0, no tremor; 1, mild tremor; 2, severe tremor.

Mentions: The wire manoeuvre tests the capacity of the mice to climb back on a horizontal wire when hung on the wire by their forelimbs. Rilmenidine-treated 171-82Q mice performed significantly better on the wire manoeuvre task from 12 until 20 weeks of age (Fig. 3A), and again there was no difference between the two groups before the start of treatment at 4 weeks. Also there was no influence of rilmenidine treatment on the performance of wild-type mice (data not shown).


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 improved overall performance at the wire manoeuvre task as well as the severity of tremors at certain time points in N171-82Q mice. (A) Mice were scored on their ability to perform the wire manoeuvre, score: 0, active grip with hind legs; 1, difficulty grasping with hind legs; 2, unable to lift hind legs; 3, falls within 30 s; 4, falls immediately. The percentage of animals obtaining each score is shown in the graphs, black bars represent rilmenidine-treated animals and white bars represent control, placebo-treated animals. Significant differences between treatment groups were seen at 12 weeks (P = 0.002), 14 weeks (P = 0.017), 16 weeks (P = 0.0246), 18 weeks (P = 0.0211) and 20 weeks (P=0.0056) of age (Mann–Whitney U test). No significant differences were seen pre-treatment at 4 weeks as well as at 22 weeks (P = 0.1495) of age. (B) The severity of tremors in N171-82Q mice was significantly improved by rilmenidine treatment at 16 weeks (P = 0.0403) and 18 weeks (P = 0.0293) of age, and a trend towards an improvement was also evident at the age of 12 weeks (P = 0.0583) in comparison to the control group. No significant differences were seen at 14 weeks (P = 0.1762), 20 weeks (P = 0.2987) and 22 weeks (P = 0.3367) of age. Score: 0, no tremor; 1, mild tremor; 2, severe tremor.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

DDQ093F3: Rilmenidine treatment improved overall performance at the wire manoeuvre task as well as the severity of tremors at certain time points in N171-82Q mice. (A) Mice were scored on their ability to perform the wire manoeuvre, score: 0, active grip with hind legs; 1, difficulty grasping with hind legs; 2, unable to lift hind legs; 3, falls within 30 s; 4, falls immediately. The percentage of animals obtaining each score is shown in the graphs, black bars represent rilmenidine-treated animals and white bars represent control, placebo-treated animals. Significant differences between treatment groups were seen at 12 weeks (P = 0.002), 14 weeks (P = 0.017), 16 weeks (P = 0.0246), 18 weeks (P = 0.0211) and 20 weeks (P=0.0056) of age (Mann–Whitney U test). No significant differences were seen pre-treatment at 4 weeks as well as at 22 weeks (P = 0.1495) of age. (B) The severity of tremors in N171-82Q mice was significantly improved by rilmenidine treatment at 16 weeks (P = 0.0403) and 18 weeks (P = 0.0293) of age, and a trend towards an improvement was also evident at the age of 12 weeks (P = 0.0583) in comparison to the control group. No significant differences were seen at 14 weeks (P = 0.1762), 20 weeks (P = 0.2987) and 22 weeks (P = 0.3367) of age. Score: 0, no tremor; 1, mild tremor; 2, severe tremor.
Mentions: The wire manoeuvre tests the capacity of the mice to climb back on a horizontal wire when hung on the wire by their forelimbs. Rilmenidine-treated 171-82Q mice performed significantly better on the wire manoeuvre task from 12 until 20 weeks of age (Fig. 3A), and again there was no difference between the two groups before the start of treatment at 4 weeks. Also there was no influence of rilmenidine treatment on the performance of wild-type mice (data not shown).

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