Hung LW, Villemagne VL, Cheng L, Sherratt NA, Ayton S, White AR, Crouch PJ, Lim S, Leong SL, Wilkins S, George J, Roberts BR, Pham CL, Liu X, Chiu FC, Shackleford DM, Powell AK, Masters CL, Bush AI, O'Keefe G, Culvenor JG, Cappai R, Cherny RA, Donnelly PS, Hill AF, Finkelstein DI, Barnham KJ. The hypoxia imaging agent CuII(atsm) is neuroprotective and improves motor and cognitive functions in multiple animal models of Parkinson's disease. J Exp Med. 2012 Apr 9;209(4):837-54. PubMed.
Recommends
Please login to recommend the paper.
Comments
Ottawa Hospital
This is an impressive study in terms of the very long follow-up data in a highly selected group of three young-onset PD patients. Collecting detailed clinical and imaging data on patients after an intervention 13 to 16 years earlier is a significant task. It is remarkable that these three individuals continued to get improvement in their PD motor symptoms from the transplants after so many years and they continued not to require any levodopa medication. However, these individuals developed increasing difficulties with the non-motor features of PD.
We need to keep in mind these were very young patients whose disease started at ~34 years old. This is rare in PD. None of them had developed a dementia after more than 25 years of disease, which would not be typical for most PD individuals. This is often the most disabling non-motor feature of PD. Although the PD control group was matched for current age, the difference in disease duration between them was 20 years and so the comparisons made between the groups need to be interpreted with caution.
The authors try to link the non-motor symptoms of these three grafted PD individuals to their low serotonergic levels as measured by DASB PET scans. Their final comment that one might consider trying to transplant serotonergic cells to replace this deficit will be met with great skepticism by most researchers. It is clear that a wide range of cells degenerate in more advanced PD. Targeting just one of these non-dopamine cell types is unlikely to reverse the many problems of advanced PD.
We have a wide variety of treatment options that currently control the motor symptoms for most PD patients. Clearly we need to understand the overall degenerative process better before we can consider future dopaminergic AND non-dopaminergic transplantation techniques.
View all comments by David GrimesBanner Sun Health Research Institute
There is a tremendous need for agents that slow or stop progression of PD. This study of CuII(atsm) by Hung and colleagues does an admirable job of reviewing a variety of preclinical models of PD and demonstrating efficacy for this class of therapeutics. In addition to demonstrating benefits in animal models, it appears to have had restorative and anti-synuclein properties as well. No overt toxicity has been seen, although long-term follow-up has not been extensive. Short- and long-term primate studies are warranted, and then, hopefully, we will see studies in humans.
Philadelphia VA Medical Center
This is a very interesting study that provides many different lines of evidence to support a role for CuII(atsm) in blocking dopaminergic cell loss in several models of PD. Given the proposed mechanism of action regarding scavenging of peroxynitrate, it should not be surprising that this agent has efficacy in MPTP-mediated models of neurodegeneration. What was somewhat more surprising were the modest benefits seen in transgenic α-synuclein models of PD.
While there are still many questions to be answered, this report certainly suggests that this novel therapeutic target and agent deserve more attention as potentially neuroprotective in PD and other neurodegenerative conditions known to involve oxidative chemistry. Even though I was involved with some of the early studies examining nitration of α-synuclein, I was not convinced that nitrative modification of α-synuclein was far enough upstream in the pathophysiologic cascade to be a useful therapeutic target. This study makes a compelling argument that this may in fact be the case. I look forward to learning more about this compound and this avenue of investigation.
Make a Comment
To make a comment you must login or register.