Abstract
Parkinson’s disease (PD) is characterized by slow progression with a long prodromal stage and the gradual evolution of both neuropsychological symptoms and subtle motor changes, preceding motor dysfunction. Thus, in order for animal models of PD to be valid, they should reproduce these characteristics of the disease. One of such models, in which neuropathology is induced by chronic injections of low doses of mitochondrial toxin rotenone, is well established in rats. However, data on this model adapted to mice remain controversial. We have designed the study to describe the timecourse of motor and non-motor symptoms during chronic subcutaneous administration of rotenone (4 mg/kg daily for 35 days) in C57BL/6 mice. We characterize the underlying neuropathological processes (dopaminergic neuron degeneration, regional brain metabolism, monoamine neurotransmitter and lipid peroxidation changes) at different timepoints: 1 day, 2 weeks and 5 weeks of daily rotenone exposure. Based on the behavioral data, we can describe three stages of pathology: cognitive changes from week 2 of rotenone exposure, subtle motor changes in week 3–4 and motor dysfunction starting roughly from week 4. Neuropathological changes in this model include a general decrease in COX activity in different areas of the brain (acute effect of rotenone) and a more specific decrease in midbrain (chronic effect), followed by significant neurodegeneration in SNpc but not VTA by the 5th week of rotenone exposure. However, we were unable to find changes in the level of monoamine neurotransmitters neither in the striatum nor in the cortex, nor in the level of lipid peroxidation in the brainstem. Thus, the gradual progression of pathology in this model is linked with metabolic changes, rather than with oxidative stress or tonic neurotransmitter release levels. Overall, this study supports the idea that a low-dose rotenone mouse model can also reproduce different stages of PD as well as rats.
Highlights
Parkinson’s disease (PD) is a chronic progressive neurodegenerative disease, affecting about 2–3% of the population over 65 years old [1,2]
Aside from motor symptoms, which are seen after 60% of dopaminergic cells in substantia nigra pars compacta (SNpc) are dead and the level of dopamine in striatum is decreased by more than 70% [4–6], PD is characterized by a plethora of neuropsychological symptoms—from depression and anxiety to cognitive decline—which usually
This study is not the first to do that, as the question of differences between rotenone action on mice and rats remains current since its first use in rat models of PD progression [14]
Summary
Parkinson’s disease (PD) is a chronic progressive neurodegenerative disease, affecting about 2–3% of the population over 65 years old [1,2]. It is characterized by the triad of motor symptoms—rigidity, bradykinesia and tremor—becoming progressively worse as the disease advances [3]. Biomedicines 2022, 10, 466 manifest earlier in the disease’s progression [7]. Most of these symptoms are still to be matched with the corresponding neuropathological mechanisms. The progression of PD demonstrates complex temporal dynamics both from the point of behavioral symptoms and underlying neuropathological cascades. Despite several factors that are found to contribute to its onset and progression, from genetic predisposition to environmental toxin exposure [8–10], the pathogenesis of sporadic PD remains largely unknown
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