This week, two papers in the July 5, 2007 issues of Neuron and Nature reported mechanistic findings that may in time bring two more weapons to the physician's arsenal in the fight against Parkinson's disease.
The root cause of Parkinson's is the death of dopamine-containing neurons in the substantia nigra. Collectively, though, multiple approaches are being attempted to combat Parkinson's. For instance, Neurologix Inc. announced encouraging results from a Phase I clinical study that used gene therapy to treat Parkinson's patients, and two papers showed the importance of residual cells to transplantation success in animal models.
The current standard treatment is L-dopa, a dopamine precursor, which raises brain dopamine levels but does not halt the course of the disease. (See BioWorld Today, June 15, 2007.)
One contributing factor to neuronal death in Parkinson's is the accumulation of free radicals in mitochondria. In the Neuron paper, researchers from the Universities of Ottawa and British Columbia detail the relationship between the neuronal kinase Cdk5 and the peroxidase Prx2.
The researchers used the neurotoxin MPTP to induce Parkinson's disease in mice. MPTP causes Parkinson-like symptoms in animals, and famously caused Parkinson's disease in a number of addicts who took a contaminated batch of synthetic heroin in the early 1980's.
The investigators found that as a consequence of the brain damage induced by MPTP, Cdk5 was activated and, in turn, switched off Prx2, which led to the accumulation of free radicals in mitochondria. Restoring Prx2 function via gene therapy prevented the death of neurons in response to MPTP.
Tissue staining experiments on the autopsy samples of the brains of several Parkinson's patients showed that they had reduced levels of Prx2 activity compared to controls, suggesting that Prx2 also is active in humans and could thus be a therapeutic target.
The authors concluded that "our findings suggest that strategies to modulate Prx2 activity serve as beneficial targets for treatment of [Parkinson's disease]. . . This is of particular importance since Cdk5 is thought to have normal beneficial roles in neurons and modulating a relevant downstream target rather than Cdk5 directly may be a better therapeutic strategy with regard to this pathway."
The Nature paper, which was published by scientists from the University of Helsinki in Finland and Tallinn University of Technology in Estonia, described a novel growth factor for neurons, which they christened "conserved dopamine neurotrophic factor" or CDNF.
In further experiments, the researchers compared the effects of CDNF to glial-derived neurotrophic factor or GDNF, the currently best-known growth factor for dopamine-containing neurons. GDNF has been used experimentally on Parkinson's patients, but its limited efficacy, combined with side effects, give the compound rather less than blockbuster potential.
The research team then used another chemical toxin, 6-hydroxydopamine, to induce neural degeneration and Parkinson's-like symptoms in mice. They found that giving mice an injection of CDNF before administering 6-hydroxydopamine prevented neural degeneration and the behavioral symptoms of Parkinson's.
The authors found that CDNF was "at least as effective" as GDNF in preventing neural death and Parkinson's symptoms in both experimental approaches, and concluded that "CDNF might be beneficial for the treatment of Parkinson's disease."