| [PMID]: | 23393146 |
| [Au] Autor: | Malik B; Nirmalananthan N; Gray AL; La Spada AR; Hanna MG; Greensmith L |
| [Ad] Dirección: | Sobell Department of Motor Neuroscience, MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. l.greensmith@ucl.ac.uk |
| [Ti] Título: | Co-induction of the heat shock response ameliorates disease progression in a mouse model of human spinal and bulbar muscular atrophy: implications for therapy. |
| [So] Fuente: | Brain;136(Pt 3):926-43, 2013 Mar. |
| [Is] ISSN: | 1460-2156 |
| [Cp] País de publicación: | England |
| [La] Idioma: | eng |
| [Ab] Resumen: | Spinal and bulbar muscular atrophy, also known as Kennedy's disease, is an adult-onset hereditary neurodegenerative disorder caused by an expansion of the polyglutamine repeat in the first exon in the androgen receptor gene. Pathologically, the disease is defined by selective loss of spinal and bulbar motor neurons causing bulbar, facial and limb weakness. Although the precise disease pathophysiology is largely unknown, it appears to be related to abnormal accumulation of the pathogenic androgen receptor protein within the nucleus, leading to disruption of cellular processes. Using a mouse model of spinal and bulbar muscular atrophy that exhibits many of the characteristic features of the human disease, in vivo physiological assessment of muscle function revealed that mice with the pathogenic expansion of the androgen receptor develop a motor deficit characterized by a reduction in muscle force, abnormal muscle contractile characteristics, loss of functional motor units and motor neuron degeneration. We have previously shown that treatment with arimoclomol, a co-inducer of the heat shock stress response, delays disease progression in the mutant superoxide dismutase 1 mouse model of amyotrophic lateral sclerosis, a fatal motor neuron disease. We therefore evaluated the therapeutic potential of arimoclomol in mice with spinal and bulbar muscular atrophy. Arimoclomol was administered orally, in drinking water, from symptom onset and the effects established at 18 months of age, a late stage of disease. Arimoclomol significantly improved hindlimb muscle force and contractile characteristics, rescued motor units and, importantly, improved motor neuron survival and upregulated the expression of the vascular endothelial growth factor which possess neurotrophic activity. These results provide evidence that upregulation of the heat shock response by treatment with arimoclomol may have therapeutic potential in the treatment of spinal and bulbar muscular atrophy and may also be a possible approach for the treatment of other neurodegenerative diseases. |
| [Mh] Términos MeSH primario: |
Proteínas de Choque Térmico/metabolismo
Respuesta al Choque Térmico/efectos de drogas
Hidroxilaminas/farmacología
Trastornos Musculares Atróficos/metabolismo
Fármacos Neuroprotectores/farmacología
|
| [Mh] Términos MeSH secundario: |
Animales
Western Blotting
Modelos Animales de Enfermedad
Progresión de la Enfermedad
Respuesta al Choque Térmico/fisiología
Masculino
Ratones
Reacción en Cadena en Tiempo Real de la Polimerasa
|
| [Pt] Tipo de publicación: | JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T |
[Nm] Nombre de substancia:
| 0 (Heat-Shock Proteins); 0 (Hydroxylamines); 0 (Neuroprotective Agents); EUT3557RT5 (arimoclomol) |
| [Em] Mes de ingreso: | 1304 |
| [Sb] Subgrupo de revista: | AIM; IM |
| [Da] Fecha de ingreso para procesamiento: | 130225 |
| [St] Status: | MEDLINE |
| [do] DOI: | 10.1093/brain/aws343 |
