Genomic and proteomic study to survey the mechanism of action of the anti-Parkinson's disease drug, rasagiline compared with selegiline, in the rat midbrain.
The novel anti-Parkinson's disease (PD) drug, rasagiline (N-propargyl-1-(R)-aminoindan), is a second generation of irreversible selective inhibitor of monoamine oxidase-B follows selegiline. In light of the recent large clinical study (phase III ADAGIO) reporting benefits in PD patients, it has been suggested that rasagiline could be the first PD treatment to receive the label neuroprotective "disease-modifying" drug. Indeed, rasagiline has been shown to have a broad neuroprotective activity against a variety of neurotoxins in preclinical models of neurodegenerative diseases and in cultured neuronal cells. In the present study, we have investigated the status of various molecular and biochemical markers in the rat midbrain following chronic treatments with rasagiline and selegiline, using proteomic and genomic analyses. Our findings demonstrated significant molecular changes induced by both drugs, at the protein and transcriptional levels, associated with neuronal differentiation, cell survival and death pathways, metabolism/oxidation stress, signaling system, and biomarkers of neurodegenerative disorders, which may be reflected in the clinical studies.
Weinreb
Orly
O
Department of Pharmacology, Technion-Faculty of Medicine, Rappaport Family Research Institute, Eve Topf Centers of Excellence for Neurodegenerative Diseases Research, Haifa, Israel. worly@tx.technion.ac.il
Amit
Tamar
T
Sagi
Yotam
Y
Drigues
Noam
N
Youdim
Moussa B H
MB
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005260:Female; D023281:Genomics / Q000379:methods; D007189:Indans / Q000494:pharmacology*; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D012642:Selegiline / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology
D000978:Antiparkinson Agents; D015415:Biomarkers; D007189:Indans; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C031967:rasagiline; D012642:Selegiline