Cunha_2017_Mol.Neurobiol_54_6356

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 mug/mouse) in C57BL6 mice. MPP(+) administration at high dose (18 mug/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 mug/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 mug/mouse increased tyrosine hydroxylase (TH) immunocontent and at 18 mug/mouse increased alpha-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 mug/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 mug/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 mug/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 mug/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.