Los niveles de FNDC del ARNm en modelos con roedores de la EH
Los niveles de FNDC del ARNm declina con la progresión de la enfermedad en modelos con roedores de la EH y son los niveles normales son restaurados con CEP-1347
Este estudio es una investigación complementaria del artículo "CEP-1347 restaura la expresión del FNDC en el ratón R6/2". Este segundo estudio sugiere que los niveles de FNDC del mensajero ARN (mARN) en la sangre podrían servir como bioindicadores. Mientras los niveles de FNDC de la proteína en sí misma no fueron detectados en sangre, los niveles del mARN resultaron detectables en modelos con roedores. Estos niveles declinaron con la edad, pero fueron restaurados a niveles normales a través del tratamiento con CEP-1347.
Si el FNDC del mARN es detectable en la sangre de aquellos que son portadores del gen, entonces se constituirían como buenos bioindicadores para determinar cuándo es necesario el tratamiento y si éste ha sido efectivo para restaurar el FNDC.
Blood level of brain-derived neurotrophic factor mRNA is progressively reduced in rodent models of Huntington's disease: Restoration by the neuroprotective compound CEP-1347
Huntington's disease (HD) is an age-related neurodegenerative disorder that is currently untreatable. A prominent feature of HD pathology is the reduction of the pro-survival neurotrophin Brain-Derived Neurotrophic Factor (BDNF). Both mRNA and protein levels of BDNF are decreased in the brains of several HD rodent models and in human HD patients. We now report for the first time that this molecular event is mirrored in blood from HD rodent models. While protein levels of BDNF are undetectable in mouse blood, mRNA levels are measurable and diminish during HD progression in transgenic mouse (R6/2) and rat models of HD. Among the eight different BDNF transcripts, only BDNF exon III is transcribed in mouse blood and its expression is progressively compromised in R6/2 mice with respect to age-matched wild-types. Assessment of BDNF mRNA in HD rat blood shows a similar result, which is reinforced by evidence that protein levels of the neurotrophin are also significantly reduced at a symptomatic stage. Finally, we demonstrate that acute and chronic treatment of R6/2 mice with CEP-1347, a mixed lineage kinase (MLK) inhibitor with neuroprotective and neurotrophic effects, leads to increased total BDNF mRNA in blood when compared to untreated R6/2 mice. Our results indicate that alterations in BDNF mRNA levels in peripheral blood are a readily accessible measurement of disease progression and drug efficacy in HD rodent models.
Molecular and Cellular Neuroscience 2008 May 10. [Epub ahead of print]