title: MPP+-Lesioned Mice: an Experimental Model of Motor, Emotional, Memory/Learning, and Striatal Neurochemical Dysfunctions.
abstract: The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces motor and nonmotor dysfunctions resembling Parkinson's disease (PD); however, studies investigating the effects of 1-methyl-4-phenylpyridinium (MPP+), an active oxidative product of MPTP, are scarce. This study investigated the behavioral and striatal neurochemical changes (related to oxidative damage, glial markers, and neurotrophic factors) 24 h after intracerebroventricular administration of MPP+(1.8-18 μg/mouse) in C57BL6 mice. MPP+administration at high dose (18 μg/mouse) altered motor parameters, since it increased the latency to leave the first quadrant and reduced crossing, rearing, and grooming responses in the open-field test and decreased rotarod latency time. MPP+administration at low dose (1.8 μg/mouse) caused specific nonmotor dysfunctions as it produced a depressive-like effect in the forced swim test and tail suspension test, loss of motivational and self-care behavior in the splash test, anxiety-like effect in the elevated plus maze test, and short-term memory deficit in the step-down inhibitory avoidance task, without altering ambulation. MPP+at doses of 1.8-18 μg/mouse increased tyrosine hydroxylase (TH) immunocontent and at 18 μg/mouse increased α-synuclein and decreased parkin immunocontent. The astrocytic calcium-binding protein S100B and glial fibrillary acidic protein (GFAP)/S100B ratio was decreased following MPP+administration (18 μg/mouse). At this highest dose, MPP+increased the ionized calcium-binding adapter molecule 1 (Iba-1) immunocontent, suggesting microglial activation. Also, MPP+at a dose of 18 μg/mouse increased thiobarbituric acid reactive substances (TBARS) and glutathione (GSH) levels and increased glutathione peroxidase (GPx) and hemeoxygenase-1 (HO-1) immunocontent, suggesting a significant role for oxidative stress in the MPP+-induced striatal damage. MPP+(18 μg/mouse) also increased striatal fibroblast growth factor 2 (FGF-2) and brain-derived neurotrophic factor (BDNF) levels. Moreover, MPP+decreased tropomyosin receptor kinase B (TrkB) immunocontent. Finally, MPP+(1.8-18 μg/mouse) increased serum corticosterone levels and did not alter acetylcholinesterase (AChE) activity in the striatum but increased it in cerebral cortex and hippocampus. Collectively, these results indicate that MPP+administration at low doses may be used as a model of emotional and memory/learning behavioral deficit related to PD and that MPP+administration at high dose could be useful for analysis of striatal dysfunctions associated with motor deficits in PD.
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, 88040-900, Brazil. mauricio.personal@gmail.com.
authors.forename: Mauricio P
authors.initials: MP
authors.lastname: Cunha
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, 88040-900, Brazil.
authors.forename: Francis L
authors.initials: FL
authors.lastname: Pazini
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, 88040-900, Brazil.
authors.forename: Vicente
authors.initials: V
authors.lastname: Lieberknecht
authors.affiliation: Laboratory of Neurosciences, National Institute for Translational Medicine, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil.
authors.forename: Josiane
authors.initials: J
authors.lastname: Budni
authors.affiliation: Department of Biochemistry, Institute of Chemistry, Universidade de São Paulo, São Paulo, SP, 05508-900, Brazil.
authors.forename: Ágatha
authors.initials: Á
authors.lastname: Oliveira
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, 88040-900, Brazil.
authors.forename: Júlia M
authors.initials: JM
authors.lastname: Rosa
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, 88040-900, Brazil.
authors.forename: Gianni
authors.initials: G
authors.lastname: Mancini
authors.affiliation: Department of Morphological Sciences, Center of Biological Science, Universidade Federal de Santa Catarina, Florianópolis, SC, 88040-900, Brazil.
authors.forename: Leidiane
authors.initials: L
authors.lastname: Mazzardo
authors.affiliation: Centro Universitário Municipal de São José, São José, SC, Brazil.
authors.forename: André R
authors.initials: AR
authors.lastname: Colla
authors.affiliation: Department of Biochemistry, Institute of Basic Health Science, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, Rio Grande do Sul, 90035-003, Brazil.
authors.forename: Marina C
authors.initials: MC
authors.lastname: Leite
authors.affiliation: Department of Physiological Sciences, Center of Biological Science, Universidade Federal de Santa Catarina, Florianópolis, SC, 88040-900, Brazil.
authors.forename: Adair R S
authors.initials: ARS
authors.lastname: Santos
authors.affiliation: Graduate Program in Health Sciences, Universidade do Sul de Santa Catarina, Pedra Branca, Palhoça, SC, 88137-270, Brazil.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Martins
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, 88040-900, Brazil.
authors.forename: Andreza F
authors.initials: AF
authors.lastname: de Bem
authors.affiliation: Department of Biochemistry, Institute of Basic Health Science, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, Rio Grande do Sul, 90035-003, Brazil.
authors.forename: Carlos Alberto S
authors.initials: CAS
authors.lastname: Gonçalves
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, 88040-900, Brazil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Farina
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, 88040-900, Brazil.
authors.forename: Ana Lúcia S
authors.initials: ALS
authors.lastname: Rodrigues
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004644:Emotions / Q000187:drug effects*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007858:Learning / Q000187:drug effects*; D008568:Memory / Q000187:drug effects*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D064568:S100 Calcium Binding Protein beta Subunit / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D064568:S100 Calcium Binding Protein beta Subunit; C579159:S100b protein, mouse; D017392:Thiobarbituric Acid Reactive Substances; C528900:glial fibrillary astrocytic protein, mouse; D000110:Acetylcholinesterase; D005978:Glutathione; D015655:1-Methyl-4-phenylpyridinium
keywords: Glia; MPP+; Neurotrophic factors; Oxidative stress; Parkinson’s disease