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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 improved grip strength in a transgenic mouse model of HD. N171-82Q mice were given rilmenidine ip injections four times a week (tg Rilm: 4, 12 and 14 weeks, n = 20; 16 weeks, n = 19; 18 weeks, n = 16; 20 weeks, n = 12; 22 weeks, n = 6 and 24 weeks, n = 2) or ip injections with the carrier substance (tg Con: 4, 12, 14 and 16 weeks, n = 20; 18 weeks, n = 17; 20 weeks, n = 12; 22 weeks, n = 6 and 24 weeks, n = 2) from 5 weeks of age. Wild-type mice were given rilmenidine or placebo injections with the same frequency (wt Rilm and wt Con, n = 5) (A) Forelimb grip strength in N171-82Q mice at 4 weeks (P = n.s.), 12–18 weeks (P < 0.0001), 20 weeks (P = 0.01), 22 weeks (P = 0.0057) and 24 weeks (P = n.s.) (by t-test). Rilmenidine treatment had no effect on grip strength in wild-type mice. (B) All limb grip strength in N171-82Q mice at 4 weeks (P = n.s.), 12 weeks (P = 0.002), 14 weeks (P < 0.0001), 16 weeks (P = 0.0015), 18 weeks (P = 0.0001), 20 weeks (P = 0.01), 22 weeks (P = 0.0129) and 24 weeks (P = n.s.) (by t-test). Error bars represent SEM.
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DDQ093F2: Rilmenidine improved grip strength in a transgenic mouse model of HD. N171-82Q mice were given rilmenidine ip injections four times a week (tg Rilm: 4, 12 and 14 weeks, n = 20; 16 weeks, n = 19; 18 weeks, n = 16; 20 weeks, n = 12; 22 weeks, n = 6 and 24 weeks, n = 2) or ip injections with the carrier substance (tg Con: 4, 12, 14 and 16 weeks, n = 20; 18 weeks, n = 17; 20 weeks, n = 12; 22 weeks, n = 6 and 24 weeks, n = 2) from 5 weeks of age. Wild-type mice were given rilmenidine or placebo injections with the same frequency (wt Rilm and wt Con, n = 5) (A) Forelimb grip strength in N171-82Q mice at 4 weeks (P = n.s.), 12–18 weeks (P < 0.0001), 20 weeks (P = 0.01), 22 weeks (P = 0.0057) and 24 weeks (P = n.s.) (by t-test). Rilmenidine treatment had no effect on grip strength in wild-type mice. (B) All limb grip strength in N171-82Q mice at 4 weeks (P = n.s.), 12 weeks (P = 0.002), 14 weeks (P < 0.0001), 16 weeks (P = 0.0015), 18 weeks (P = 0.0001), 20 weeks (P = 0.01), 22 weeks (P = 0.0129) and 24 weeks (P = n.s.) (by t-test). Error bars represent SEM.

Mentions: Grip strength was quantified using a grip strength meter from 12 to 24 weeks. Rilmenidine-treated 171-82Q mice displayed significant improved forelimb grip strength (Fig. 2A) and all limbs grip strength (Fig. 2B) from 12 to 22 weeks of age. There was no influence of rilmenidine treatment on the performance of wild-type mice. Also there was no difference between the two groups in forelimb or all limb grip strength before treatment commenced at 4 weeks of age.


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 improved grip strength in a transgenic mouse model of HD. N171-82Q mice were given rilmenidine ip injections four times a week (tg Rilm: 4, 12 and 14 weeks, n = 20; 16 weeks, n = 19; 18 weeks, n = 16; 20 weeks, n = 12; 22 weeks, n = 6 and 24 weeks, n = 2) or ip injections with the carrier substance (tg Con: 4, 12, 14 and 16 weeks, n = 20; 18 weeks, n = 17; 20 weeks, n = 12; 22 weeks, n = 6 and 24 weeks, n = 2) from 5 weeks of age. Wild-type mice were given rilmenidine or placebo injections with the same frequency (wt Rilm and wt Con, n = 5) (A) Forelimb grip strength in N171-82Q mice at 4 weeks (P = n.s.), 12–18 weeks (P < 0.0001), 20 weeks (P = 0.01), 22 weeks (P = 0.0057) and 24 weeks (P = n.s.) (by t-test). Rilmenidine treatment had no effect on grip strength in wild-type mice. (B) All limb grip strength in N171-82Q mice at 4 weeks (P = n.s.), 12 weeks (P = 0.002), 14 weeks (P < 0.0001), 16 weeks (P = 0.0015), 18 weeks (P = 0.0001), 20 weeks (P = 0.01), 22 weeks (P = 0.0129) and 24 weeks (P = n.s.) (by t-test). Error bars represent SEM.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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DDQ093F2: Rilmenidine improved grip strength in a transgenic mouse model of HD. N171-82Q mice were given rilmenidine ip injections four times a week (tg Rilm: 4, 12 and 14 weeks, n = 20; 16 weeks, n = 19; 18 weeks, n = 16; 20 weeks, n = 12; 22 weeks, n = 6 and 24 weeks, n = 2) or ip injections with the carrier substance (tg Con: 4, 12, 14 and 16 weeks, n = 20; 18 weeks, n = 17; 20 weeks, n = 12; 22 weeks, n = 6 and 24 weeks, n = 2) from 5 weeks of age. Wild-type mice were given rilmenidine or placebo injections with the same frequency (wt Rilm and wt Con, n = 5) (A) Forelimb grip strength in N171-82Q mice at 4 weeks (P = n.s.), 12–18 weeks (P < 0.0001), 20 weeks (P = 0.01), 22 weeks (P = 0.0057) and 24 weeks (P = n.s.) (by t-test). Rilmenidine treatment had no effect on grip strength in wild-type mice. (B) All limb grip strength in N171-82Q mice at 4 weeks (P = n.s.), 12 weeks (P = 0.002), 14 weeks (P < 0.0001), 16 weeks (P = 0.0015), 18 weeks (P = 0.0001), 20 weeks (P = 0.01), 22 weeks (P = 0.0129) and 24 weeks (P = n.s.) (by t-test). Error bars represent SEM.
Mentions: Grip strength was quantified using a grip strength meter from 12 to 24 weeks. Rilmenidine-treated 171-82Q mice displayed significant improved forelimb grip strength (Fig. 2A) and all limbs grip strength (Fig. 2B) from 12 to 22 weeks of age. There was no influence of rilmenidine treatment on the performance of wild-type mice. Also there was no difference between the two groups in forelimb or all limb grip strength before treatment commenced at 4 weeks of age.

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