Explaining ADAGIO: A critical review of the biological basis for the clinical effects of rasagiline

Abstract

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.

Acute and chronic cognitive effects of levodopa and dopamine agonists on patients with Parkinson’s disease: a review

“…This issue is of particular clinical interest considering that since the time of clinical diagnosis of PD many patients present a mild cognitive impairment: is this cognitive feature worsened or improved by the prolonged dopaminergic therapy? In addition to the potential risk of inducing dyskinesia and behavioral side effects such as impulse control disorders [Weintraub et al 2010], also cognitive effects of prolonged dopaminergic treatments should be taken into account by clinicians in order to anticipate or to delay their prescription to PD patients, possibly adopting other drugs with possible effects of neuroprotection and cognitive enhancement, as the selective monoamine oxidase type-B inhibitor rasagiline [Elmer et al 2006;Hanagasi et al 2011;Jenner and Langston, 2011].…”

Pathogenesis-Targeted, Disease-Modifying Therapies in Parkinson Disease

“…The failure of the 2 mg dose and the success of the 1 mg dose in all three predefined variables have made the interpretation of these results regarding disease modification difficult. Further biological plausibility for the modifying effects of rasagiline have been proposed based on the evidence that mitochondrial impairment contributes to dopaminergic neuronal loss in PD and rasagiline has been found to affect numerous mitochondrial mechanisms that prevent apoptotic cell death [13].…”

Rasagiline prevents cyclosporine A-sensitive superoxide flashes induced by PK11195, the initial signal of mitochondrial membrane permeabilization and apoptosis

“…Cyclosporine A IMM Inner mitochondrial membrane MPT Membrane permeability transition mPTP Mitochondrial permeability transition pore OMM Outer mitochondrial membrane TSPO The outer membrane translocator protein 18 kDa Rasagiline, an inhibitor of type B monoamine oxidase (MAO-B), protects neurons from programmed cell death in cellular and animal models, and some beneficial effects were presented on the progression of Parkinson's disease in clinical trials (Finberg 2010;Jenner and Langston 2011). The neuroprotective function is ascribed to the anti-apoptotic activity through the stabilization of mitochondrial membrane, induction of genes coding anti-apoptotic Bcl-2 and pro-survival neurotrophic factors, and regulation of intracellular signal pathways (Bar-Am et al 2016;Naoi et al 2013).…”