Funding agencies: This study was funded by Teva Pharmaceuticals, Teva Neuroscience, and H. Lundbeck A/S.
Article first published online: 23 SEP 2011
Copyright © 2011 Movement Disorder Society
Volume 26, Issue 13, pages 2316–2323, November 2011
How to Cite
Jenner, P. and Langston, J. W. (2011), Explaining ADAGIO: A critical review of the biological basis for the clinical effects of rasagiline. Mov. Disord., 26: 2316–2323. doi: 10.1002/mds.23926
Relevant conflicts of interest/financial disclosures: Peter Jenner reports receiving consulting fees from Merck Serono, Teva, Lundbeck, FP Pharmaceuticals; Orion Pharma; lecture fees from Merck Serono, Teva, Lundbeck, Boehringer Ingelheim, GSK, Novartis, UCB, Orion Pharma; and grant support from Parkinson's UK, Cure Parkinson Foundation, Rosetrees Trust. J. William Langston reports receiving consulting and lecture fees from Teva and consulting fees from Merck Serono, Lundbeck, and Iperion, as well as grant support from the Michael J. Fox Foundation, Department of Defense, and the California Institute for Regenerative Medicine.
Full financial disclosures and author roles may be found in the online version of this article.
- Issue published online: 22 NOV 2011
- Article first published online: 23 SEP 2011
- Manuscript Accepted: 11 JUL 2011
- Manuscript Revised: 5 JUL 2011
- Manuscript Received: 26 APR 2011
- Parkinson's disease;
The ADAGIO study demonstrated a symptomatic benefit for rasagiline in early Parkinson's disease (PD) and suggested a disease-modifying effect. Evidence indicates that mitochondrial dysfunction plays a role in the pathogenesis of PD and that this may be the site of effect for rasagiline. In this systematic review, evidence for the role of mitochondria in the pathogenesis of PD are reviewed in light of other proposed mechanisms of neuronal degeneration and the actions of rasagiline and its component parts, namely propargylamine and the metabolite, aminoindan. Evidence for the role of mitochondria in the pathogenesis and treatment of PD are reviewed in light of other proposed mechanisms of neuronal degeneration and clinical actions of rasagiline. Monoamine oxidase B (MAO-B) located in the outer mitochondrial membrane controls dopamine metabolism in early PD, and this is the likely location for the symptomatic action of rasagiline. Accumulating evidence indicates that mitochondrial impairment contributes to dopaminergic neuronal loss in PD, either directly or through other mechanisms such as oxidative stress or protein misfolding. Further rasagiline affects numerous mitochondrial mechanisms that prevent apoptotic cell death including prevention of opening of the mitochondrial transition pore, decreased release of cytochrome C, alterations in pro-antiapoptotic genes and proteins, and the nuclear translocation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Thus, the functional neuroprotective actions of rasagiline may not be dependent on MAO-B inhibition, but rather may involve actions of the propargylamine moiety and the aminoindan metabolite. An accumulating body of literature indicates a mitochondrial site of action for rasagiline and highlights the neuroprotective action of the drug, providing strong biological plausibility for disease-modifying effects of the drug such as those observed in ADAGIO. © 2011 Movement Disorder Society