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Compound Found That Stops Neurodegeneration in Mice

By BiotechDaily International staff writers
Posted on 23 Oct 2013
British researchers, who in 2012 identified a key pathway leading to brain cell death in mice, have used an orally administered compound to block that pathway, preventing neurodegeneration in the lab mice.

The scientists, from the Medical Research Council (MRC; London, UK; www.mrc.ac.uk) toxicology unit at the University of Leicester (UK; www.le.ac.uk), had found earlier that the accumulation of misfolded proteins in the brains of mice with prion disease overactivates a natural defense mechanism in cells, which switches off the production of new proteins. This process would typically turn back “on” again, but in these mice, the continual build-up of deformed protein keeps the switch turned “off.” This is the trigger point leading to brain cell death, as the key proteins essential for nerve cell survival stop being made.

The investigators first injected a protein that arrested the “off” switch of the pathway into a small region of the brain, and by doing this were able to restore protein production, and halt the neurodegeneration. The brain cells were protected, and protein levels and synaptic transmission were restored allowing the mice to live longer. This led the scientists to predict that compounds able to block this pathway would also protect brain cells.

In the new study, published October 9, 2013, in the journal Science Translational Medicine, the researchers gave by mouth a compound against the pathway to prion-infected mice, hoping to block the off-switch in the same way. The compound, which had originally been developed by GlaxoSmithKline (London, UK) for a different reason, was able to enter the brain from the bloodstream and halt the disease, throughout the whole brain. However, this compound, despite protecting the brain, also produced weight loss in the mice and mild diabetes, due to damage to the pancreas.

The researchers studied mice with prion disease because these mouse models currently provide the best animal representation of human neurodegenerative disorders in which the build-up of misshapen proteins is tied to brain cell death. These include Parkinson’s and Alzheimer’s as well as prion diseases. Another study in the journal Nature Neuroscience published in September 2013 emphasized that this pathway could become a potential therapeutic target in treating Alzheimer’s.

Prof. Giovanna Mallucci, who led the team, said, “Our previous study predicted that this pathway could be a target for treatment to protect brain cells in neurodegenerative disease. So we administered a compound that blocks it to mice with prion disease. We were extremely excited when we saw the treatment stop the disease in its tracks and protect brain cells, restoring some normal behaviors and preventing memory loss in the mice. We’re still a long way from a usable drug for humans—this compound had serious side effects. But the fact that we have established that this pathway can be manipulated to protect against brain cell loss first with genetic tools and now with a compound, means that developing drug treatments targeting this pathway for prion and other neurodegenerative diseases is now a real possibility.”

Prof. Hugh Perry, chair of the MRC’s Neuroscience and Mental Health Board, said, “Misshapen proteins in prion diseases and other human neurodegenerative disorders, such as Alzheimer’s and Parkinson's, also over-activate this fundamental pathway controlling protein synthesis in the brains of patients. Despite the toxicity of the compound used, this study indicates that, in mice at least, we now have proof-of-principle of a therapeutic pathway that can be targeted. This might eventually aid the development of drugs to treat people suffering from dementias and other devastating neurodegenerative diseases.”

Related Links:

Medical Research Council
University of Leicester



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