| RRC ID |
6361
|
| 著者 |
Giacomotto J, Pertl C, Borrel C, Walter MC, Bulst S, Johnsen B, Baillie DL, Lochmüller H, Thirion C, Ségalat L.
|
| タイトル |
Evaluation of the therapeutic potential of carbonic anhydrase inhibitors in two animal models of dystrophin deficient muscular dystrophy.
|
| ジャーナル |
Hum Mol Genet
|
| Abstract |
Duchenne Muscular Dystrophy is an inherited muscle degeneration disease for which there is still no efficient treatment. However, compounds active on the disease may already exist among approved drugs but are difficult to identify in the absence of cellular models. We used the Caenorhabditis elegans animal model to screen a collection of 1000 already approved compounds. Two of the most active hits obtained were methazolamide and dichlorphenamide, carbonic anhydrase inhibitors widely used in human therapy. In C. elegans, these drugs were shown to interact with CAH-4, a putative carbonic anhydrase. The therapeutic efficacy of these compounds was further validated in long-term experiments on mdx mice, the mouse model of Duchenne Muscular Dystrophy. Mice were treated for 120 days with food containing methazolamide or dichlorphenamide at two doses each. Musculus tibialis anterior and diaphragm muscles were histologically analyzed and isometric muscle force was measured in M. extensor digitorum longus. Both substances increased the tetanic muscle force in the treated M. extensor digitorum longus muscle group, dichlorphenamide increased the force significantly by 30%, but both drugs failed to increase resistance of muscle fibres to eccentric contractions. Histological analysis revealed a reduction of centrally nucleated fibers in M. tibialis anterior and diaphragm in the treated groups. These studies further demonstrated that a C. elegans-based screen coupled with a mouse model validation strategy can lead to the identification of potential pharmacological agents for rare diseases.
|
| 巻・号 |
18(21)
|
| ページ |
4089-101
|
| 公開日 |
2009-11-1
|
| DOI |
10.1093/hmg/ddp358
|
| PII |
ddp358
|
| PMID |
19648295
|
| MeSH |
Animals
Caenorhabditis elegans / drug effects
Caenorhabditis elegans / genetics
Caenorhabditis elegans / physiology
Caenorhabditis elegans Proteins / genetics
Caenorhabditis elegans Proteins / metabolism
Carbonic Anhydrase Inhibitors / metabolism
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / genetics
Carbonic Anhydrases / metabolism
Dichlorphenamide / pharmacology
Disease Models, Animal*
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Dystrophin / deficiency*
Dystrophin / genetics
Humans
Methazolamide / pharmacology
Mice
Mice, Inbred mdx
Motor Activity
Muscle Contraction / drug effects
Muscle, Skeletal / drug effects
Muscle, Skeletal / pathology
Muscle, Skeletal / physiopathology
Muscular Dystrophy, Animal / genetics
Muscular Dystrophy, Animal / physiopathology
Muscular Dystrophy, Animal / prevention & control*
RNA Interference
Time Factors
|
| IF |
5.101
|
| 引用数 |
25
|
|
WOS 分野
|
GENETICS & HEREDITY
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| リソース情報 |
| 線虫 |
tm2805 |
