title: Neuropathological and behavioral changes induced by various treatment paradigms with MPTP and 3-nitropropionic acid in mice: towards a model of striatonigral degeneration (multiple system atrophy).
abstract: We characterized two models of dual nigral and striatal lesions replicating the lesion pattern of striatonigral degeneration, the neuropathological hallmark of parkinsonism associated with multiple system atrophy (SND/MSA-P). For this purpose, we used systemic administration of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and 3-nitropropionic acid (3-NP) in C57BL mice. One group of animals was first injected with MPTP followed by 3NP (MPTP+3-NP model). In the second group 3-NP was injected first, followed by MPTP (3-NP+MPTP model). The behavioral and neuropathological characteristics of these two models were compared to those observed after single 3-NP or MPTP intoxication. Results showed that, compared to control mice, spontaneous nocturnal locomotor activity was preserved in the MPTP+3-NP model, whereas it was reduced by 27% ( P<0.05) in the 3-NP+MPTP model and in animals treated with either 3-NP (27%, P<0.05) or MPTP (23%, P<0.05) alone. Quantitative histological evaluation based on Nissl staining and DARPP-32 immunohistochemistry revealed that 3-NP alone and 3-NP+MPTP treatment produced a marked (greater than 50%) loss of striatal neurons, whereas MPTP+3-NP treatment attenuated loss of striatal neurons by 43%. Further, loss of tyrosine hydroxylase-positive neurons in substantia nigra pars compacta (SNc) was attenuated after 3-NP+MPTP treatment compared to that observed after MPTP (40% vs 74%, P<0.001) and MPTP+3NP treatment (55% vs 74%, P<0.01). Our results show that MPTP-induced nigral lesions attenuate 3-NP toxicity and, reciprocally, that 3-NP-induced striatal lesions reduce MPTP toxicity. This suggests that complex integrative mechanisms are likely to regulate the vulnerability of the striatum and SNc to cell death in SND/MSA-P.
authors.affiliation: Department of Neurology, University Hospital of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: Nadia
authors.initials: N
authors.lastname: Stefanova
authors.forename: Zoe
authors.initials: Z
authors.lastname: Puschban
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Fernagut
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Brouillet
authors.forename: François
authors.initials: F
authors.lastname: Tison
authors.forename: Markus
authors.initials: M
authors.lastname: Reindl
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Jellinger
authors.forename: Werner
authors.initials: W
authors.lastname: Poewe
authors.forename: Gregor K
authors.initials: GK
authors.lastname: Wenning
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D015259:Dopamine Agents; D004347:Drug Interactions; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D020955:Striatonigral Degeneration / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology* / Q000523:psychology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D015259:Dopamine Agents; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; C015392:3-nitropropionic acid