Is the treatment of Parkinson’s disease possible with a new neurotrophic factor in the future?
Parkinson’s disease is a degenerative brain disease characterized by the loss of dopamine neurons in the midbrain-area called Substantia Nigra. The research group led by professor Mart Saarma, Director of the Institute of Biotechnology, University of Helsinki, has discovered a novel neurotrophic factor CDNF (Conserved Dopamine Neurotrophic Factor). CDNF was shown to protect and even rescue damaged dopamine neurons in an experimental model of Parkinson’s disease in studies performed by the research group of professor Raimo K. Tuominen, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland. More importantly, also the function of the neurons was recovered after an experimental lesion of the dopamine neurons in Substantia Nigra.
The findings of this research may be of great importance for the development of new treatment strategies for Parkinson’s disease. The results of this study will be published in “Nature” on July 5th, 2007.
Approximately one percent of people aged over 60 get Parkinson’s disease all over the World. The demographic change with increasing number of elderly people will lead in doubling of the number of Parkinsonian patients also in Finland during 2005 – 2030. Typical symptoms in Parkinson’s disease are those of muscle rigidity, tremor, and slowness of movement. They are a consequence of the degeneration of dopamine nerves projecting from Substantia Nigra to Caudate Putamen (also called Striatum). The clinical symptoms manifest when approximately 70 % of the dopamine nerves have been destroyed. Degeneration of the dopamine nerves progresses slowly, and in time the difficulties in movement becomes a major factor reducing the quality of life of these patients.
Current drug treatment of Parkinson’s disease aims at increasing dopamine concentration and / or activation of dopamine receptors in the brain. Due to the progression of the nerve degeneration the drug therapy gradually becomes less effective. Neurotrophic factors which could slow down or even halt the progression of the degeneration of dopamine nerves have been in the focus as a possible new treatment for Parkinson’s disease. Glial cell- line derived neurotrophic fctor (GDNF) is one example of such a promising growth factor. Indeed, it was shown to have beneficial effects in a clinical trial in Parkinsonian patients suffering from severe symptoms. However, due to adverse effects the clinical trials have been stopped, even though some of the patients would have continued the therapy. Even so, the clinical trials on GDNF gave the proof of concept for the use of neurotrophic factorstreatment of neurodegenerative diseases. Therefore it is very important to search for new growth factors with similar efficacy as GDNF, but with better tolerability.
Conserved dopamine neurotrophic (CDNF) factor discovered and characterized in this study is well conserved in the evolution. It belongs to a CDNF/MANF family of proteins, which is the first evolutionarily conserved family of neurotrophic factors having a representative also in invertebrate animals (MANF = mesencephalic astrocyte derived neurotrophic factor).
In an experimental model of Parkinson’s disease, a neurotoxin 6-OHDA was injected on one side of the brain into the striatum of rats. This toxin causes a progressive degeneration of dopamine nerves similar to that observed in Parkinsons disease. Upon activation of dopamine nerves of the brain by drugs, these animals show a movement disorder, a circling behaviour, which reflects an imbalance of dopamine activity of the brain hemispheres.
A single injection of CDNF six hours before the toxin delivery into the striatum significantly prevented the degeneration of dopamine nerves in the brain and also the turning behavior was normalized. When administered four weeks after the toxin, situation mimicking a progression of the nerve degeneration in patients, injection of CDNF into Striatum was able to prevent the degeneration of dopaminergic neurons and cure the behavioral imbalance.
The results of the present study show that CDNF is a very promising new neurotrophic factor with a significant neuroprotective and neurorestorative effects on dopamine nerves in the brain. It may have significant potential in the treatment of Parkinson’s disease in the future as a neuro protective or even neurorestorative therapy.
University of Helsinki. July 2007.