title: BDNF levels are increased by aminoindan and rasagiline in a double lesion model of Parkinson׳s disease.
abstract: The anti-Parkinsonian drug rasagiline is a selective, irreversible inhibitor of monoamine oxidase and is used in the treatment of Parkinson׳s disease (PD). Its postulated neuroprotective effects may be attributed to MAO inhibition, or to its propargylamine moiety. The major metabolite of rasagiline, aminoindan, has shown promising neuroprotective properties in vitro but there is a paucity of studies investigating in vivo effects of this compound. Therefore, we examined neuroprotective effects of rasagiline and its metabolite aminoindan in a double lesion model of PD. Male Fisher 344 rats received i.p. injections of the noradrenergic neurotoxin DSP-4 and intra-striatal stereotaxic microinjections of the dopamine neurotoxin 6-OHDA. Saline, rasagiline or aminoindan (3mg/kg/day s.c.) were delivered via Alzet minipumps for 4 weeks. Rats were then tested for spontaneous locomotion and a novel object recognition task. Following behavioral testing, brain tissue was processed for ELISA measurements of growth factors and immunohistochemistry. Double-lesioned rats treated with rasagiline or aminoindan had reduced behavioral deficits, both in motor and cognitive tasks compared to saline-treated double-lesioned rats. BDNF levels were significantly increased in the hippocampus and striatum of the rasagiline- and aminoindan-lesioned groups compared to the saline-treated lesioned group. Double-lesioned rats treated with rasagiline or aminoindan exhibited a sparing in the mitochondrial marker Hsp60, suggesting mitochondrial involvement in neuroprotection. Tyrosine hydroxylase (TH) immunohistochemistry revealed a sparing of TH-immunoreactive terminals in double-lesioned rats treated with rasagiline or aminoindan in the striatum, hippocampus, and substantia nigra. These data provide evidence of neuroprotection by aminoindan and rasagiline via their ability to enhance BDNF levels.
authors.affiliation: Department of Neurosciences and the Center on Aging, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Ledreux
authors.affiliation: Department of Neurosciences and the Center on Aging, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Boger
authors.affiliation: Department of Neurology, Medical University of South Carolina, Charleston, SC, USA; Neurology Service, Ralph H. Johnson VA Medical Center, Charleston, SC, USA.
authors.forename: Vanessa K
authors.initials: VK
authors.lastname: Hinson
authors.affiliation: Psychology and Program in Neuroscience, College of Charleston, Charleston, SC, USA.
authors.forename: Kelsey
authors.initials: K
authors.lastname: Cantwell
authors.affiliation: Department of Neurosciences and the Center on Aging, Medical University of South Carolina, Charleston, SC, USA. Electronic address: granholm@musc.edu.
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Granholm
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001596:Benzylamines / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D018834:Chaperonin 60 / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D007189:Indans / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D001596:Benzylamines; D019208:Brain-Derived Neurotrophic Factor; D018834:Chaperonin 60; D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; C031967:rasagiline; D008995:Monoamine Oxidase; C012102:DSP 4; D004298:Dopamine; D009638:Norepinephrine
keywords: Cognition; Dopamine; Monoamine oxidase inhibitors; Neuroprotection; Norepinephrine; Parkinson׳s disease