Rasagiline is neuroprotective in a transgenic model of multiple system atrophy.
Rasagiline is a novel selective irreversible monoamine oxidase-B (MAO-B) inhibitor recently introduced for the symptomatic treatment of Parkinson disease. Like other propargylamines rasagiline has also shown neuroprotective effects independent of MAO-B-inhibition in various in vitro and in vivo models. The present study was performed to test the potential of rasagiline as a disease-modifying agent in multiple system atrophy (MSA) using a transgenic mouse model previously described by our group. (PLP)-alpha-synuclein transgenic mice featuring glial cytoplasmic inclusion pathology underwent 3-nitropropionic acid intoxication to model full-blown MSA-like neurodegeneration. Two doses of rasagiline were used (0.8 and 2.5 mg/kg) for a treatment period of 4 weeks. Rasagiline-treated animals were compared to placebo saline-treated mice by evaluation of motor behaviour and neuropathology. Motor behavioural tests including pole test, stride length test and general motor score evaluation showed improvements in motor deficits associated with 2.5 mg/kg rasagiline therapy. Immunohistochemistry and histology showed significant reduction of 3-NP-induced neuronal loss in striatum, substantia nigra pars compacta, cerebellar cortex, pontine nuclei and inferior olives of MSA mice receiving 2.5 mg/kg rasagiline. The results of the study indicate that rasagiline confers neuroprotection in a transgenic mouse model of MSA and may therefore be considered a promising disease-modifying candidate for human MSA.
Stefanova
Nadia
N
Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. Nadia.Stefanova@i-med.ac.at
Poewe
Werner
W
Wenning
Gregor K
GK
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007189:Indans / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D019578:Multiple System Atrophy / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D018991:Myelin Proteolipid Protein / Q000235:genetics; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009574:Nitro Compounds; D011422:Propionates; D011597:Psychomotor Performance / Q000187:drug effects; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D007189:Indans; D018991:Myelin Proteolipid Protein; D018696:Neuroprotective Agents; D009574:Nitro Compounds; C497929:Ppp1r1b protein, mouse; D011422:Propionates; D051844:alpha-Synuclein; C031967:rasagiline; D014446:Tyrosine 3-Monooxygenase; C015392:3-nitropropionic acid