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MPP+-Lesioned Mice: an Experimental Model of Motor, Emotional, Memory/Learning, and Striatal Neurochemical
Mauricio P Cunha1, Francis L Pazini2, Vicente Lieberknecht2
1Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, 88040-900, Brazil. mauricio.personal@gmail.com.
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.
Insights
The neurotoxin 1-methyl-4-phenylpyridinium (MPP+) induces Parkinson's disease-like motor and non-motor symptoms in mice. Low doses cause emotional and memory deficits, while high doses induce motor impairments and striatal damage.
Area of Science:
- Neuroscience
- Neuropharmacology
- Parkinson's Disease Research
Background:
- 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that causes Parkinsonian symptoms.
- The active oxidative metabolite of MPTP, 1-methyl-4-phenylpyridinium (MPP+), is less studied.
- Understanding MPP+'s effects is crucial for modeling Parkinson's disease (PD).
Purpose of the Study:
- To investigate the behavioral and neurochemical effects of intracerebroventricular MPP+ administration in mice.
- To assess dose-dependent motor and non-motor dysfunctions induced by MPP+.
- To analyze striatal changes related to oxidative stress, glial markers, and neurotrophic factors.
Main Methods:
- Intracerebroventricular administration of MPP+ (1.8-18 μg/mouse) to C57BL6 mice.
- Behavioral testing including open-field, rotarod, forced swim, tail suspension, splash, elevated plus maze, and step-down inhibitory avoidance tasks.
- Striatal tissue analysis for tyrosine hydroxylase (TH), α-synuclein, parkin, S100B, GFAP, Iba-1, TBARS, GSH, GPx, HO-1, FGF-2, BDNF, TrkB, and AChE.
Main Results:
- High-dose MPP+ (18 μg/mouse) impaired motor function and altered TH, α-synuclein, and parkin levels.
- Low-dose MPP+ (1.8 μg/mouse) induced non-motor deficits including depression-like behavior, anxiety, and memory impairment.
- MPP+ induced oxidative stress, microglial activation, altered neurotrophic factor expression, and increased corticosterone levels.
Conclusions:
- Low-dose MPP+ serves as a valuable model for studying emotional and memory deficits in PD.
- High-dose MPP+ is useful for investigating striatal dysfunctions and motor deficits associated with PD.
- MPP+ administration reveals complex neurochemical and behavioral changes relevant to Parkinson's disease pathogenesis.
