CEP-1347 restores BDNF expression in the R6/2 mice

HD Lighthouse Contributing Editor's Comment: 

A drug developed to inhibit apoptosis (programmed cell death) has emerged as a candidate for the HD research pipeline. CEP-1347 was administered to RD6/2 HD mice over a four week period.  Motor symptoms improved and levels of brain derived neurotrophic factor (BDNF) were increased.  BDNF is a protein in the brain which protects striatal neurons and facilitates neuogenesis, the growth of new neurons. The authors also found that CEP-1347 reduced neurotoxicity in cell models and in drosophila.

More preclinical research needs to be done; in future research, the drug will be administered over a longer period of time to determine whether survival time is increased.  More work is also planned to determine the precise mechanisms involved. However, the research to date is encouraging because of the effect on BDNF and because the drug was shown to be safe and well-tolerated in Parkinson’s patients.  Although it was found to be ineffective in Parkinson’s, it appears promising for Huntington’s Disease.

As the authors point out, there is good evidence for a decrease in BDNF as a major pathology in Huntington’s Disease.  Dr. Elena Cattaneo and her colleagues have shown how the huntingtin’s protein interferes with gene transcription. In HD, a repressor protein known as REST enters the cell’s nucleus and suppresses key genes such as the one for BDNF.  Strikingly, a mouse model in which the gene for BDNF has been knocked out more closely reproduces the gene transcription problems in HD than in any of the HD mouse models.  Other compounds which increase BDNF, such as cysteamine and several SSRI antidepressants have been found to be helpful in HD mouse models.

CEP-1347 was developed as an anti-apoptosis drug by Cephalon pharmaceutical company.  It is an inhibitor of mixed lineage kinases that are involved in activating the c-Jun N-terminal kinase (JNK) pathway which leads to apoptosis.  It also activates the extracellular signal-regulated kinanse (ERK) pathway.  The role of this pathway is more complex but its activation appears to be neuroprotective in HD.  BDNF is a downstream target of the ERK pathway.

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 09-19-2008

Leslie Michels Thompson, Ph.D.

CEP-1347 reduces mutant huntingtin-associated neurotoxicity and restores BDNF levels in R6/2 mice

Barbara L. Apostol, Danielle A. Simmons, Chiara Zuccato, Katalin Illes, Judit Pallos, Malcolm Casale, Paola Conforti, Catarina Ramos, Margaret Roarke, Satish Kathuria, Elena Cattaneo, J. Lawrence Marsh, Leslie Michels Thompson.

Huntington's disease (HD) is a devastating neurodegenerative disorder caused by an expanded polyglutamine repeat within the protein Huntingtin (Htt). We previously reported that mutant Htt expression activates the ERK1/2 and JNK pathways [Apostol, B.L., Illes, K., Pallos, J., Bodai, L., Wu, J., Strand, A., Schweitzer, E.S., Olson, J.M., Kazantsev, A., Marsh, J.L., Thompson, L.M., 2006. Mutant huntingtin alters MAPK signaling pathways in PC12 and striatal cells: ERK1/2 protects against mutant huntingtin-associated toxicity. Hum. Mol. Genet. 15, 273–285]. Chemical and genetic modulation of these pathways promotes cell survival and death, respectively. Here we test the ability of two closely related compounds, CEP-11004 and CEP-1347, which inhibit Mixed Lineage Kinases (MLKs) and are neuroprotective, to suppress mutant Htt-mediated pathogenesis in multiple model systems. CEP-11004/CEP-1347 treatment significantly decreased toxicity in mutant Htt-expressing cells that evoke a strong JNK response. However, suppression of cellular dysfunction in cell lines that exhibit only mild Htt-associated toxicity and little JNK activation was associated with activation of ERK1/2. These compounds also reduced neurotoxicity in immortalized striatal neurons from mutant knock-in mice and Drosophila expressing a mutant Htt fragment. Finally, CEP-1347 improved motor performance in R6/2 mice and restored expression of BDNF, a critical neurotrophic factor that is reduced in HD. These studies suggest a novel therapeutic approach for a currently untreatable neurodegenerative disease, HD, via CEP-1347 up-regulation of BDNF.

Source: Molecular and Cellular Neuroscience 2008 April 24. [Epub ahead of print]