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The Progressive BSSG Rat Model of Parkinson's: Recapitulating Multiple Key Features of the Human Disease.

Van Kampen JM, Baranowski DC, Robertson HA, Shaw CA, Kay DG - PLoS ONE (2015)

Bottom Line: Locomotor deficits developed gradually over time, initially appearing as locomotor asymmetry and developing into akinesia/bradykinesia, which was reversed by levodopa treatment.In addition to the progressive loss of TH+ cells in the substantia nigra, the appearance of proteinase K-resistant intracellular α-synuclein aggregates was also observed to develop progressively, appearing first in the olfactory bulb, then the striatum, the substantia nigra and, finally, hippocampal and cortical regions.The slowly progressive nature of this model, together with its construct, face and predictive validity, make it ideal for the screening of potential neuroprotective therapies for the treatment of PD.

View Article: PubMed Central - PubMed

Affiliation: Neurodyn Inc., 550 University Ave, Charlottetown, Prince Edward Island, C1A 4P3, Canada; Dept. Biomedical Science, University of Prince Edward Island, 550 University Ave, Charlottetown, Prince Edward Island, C1A 4P3, Canada.

ABSTRACT
The development of effective neuroprotective therapies for Parkinson's disease (PD) has been severely hindered by the notable lack of an appropriate animal model for preclinical screening. Indeed, most models currently available are either acute in nature or fail to recapitulate all characteristic features of the disease. Here, we present a novel progressive model of PD, with behavioural and cellular features that closely approximate those observed in patients. Chronic exposure to dietary phytosterol glucosides has been found to be neurotoxic. When fed to rats, β-sitosterol β-d-glucoside (BSSG) triggers the progressive development of parkinsonism, with clinical signs and histopathology beginning to appear following cessation of exposure to the neurotoxic insult and continuing to develop over several months. Here, we characterize the progressive nature of this model, its non-motor features, the anatomical spread of synucleinopathy, and response to levodopa administration. In Sprague Dawley rats, chronic BSSG feeding for 4 months triggered the progressive development of a parkinsonian phenotype and pathological events that evolved slowly over time, with neuronal loss beginning only after toxin exposure was terminated. At approximately 3 months following initiation of BSSG exposure, animals displayed the early emergence of an olfactory deficit, in the absence of significant dopaminergic nigral cell loss or locomotor deficits. Locomotor deficits developed gradually over time, initially appearing as locomotor asymmetry and developing into akinesia/bradykinesia, which was reversed by levodopa treatment. Late-stage cognitive impairment was observed in the form of spatial working memory deficits, as assessed by the radial arm maze. In addition to the progressive loss of TH+ cells in the substantia nigra, the appearance of proteinase K-resistant intracellular α-synuclein aggregates was also observed to develop progressively, appearing first in the olfactory bulb, then the striatum, the substantia nigra and, finally, hippocampal and cortical regions. The slowly progressive nature of this model, together with its construct, face and predictive validity, make it ideal for the screening of potential neuroprotective therapies for the treatment of PD.

No MeSH data available.


Related in: MedlinePlus

BSSG triggers hippocampal and cortical synaptic atrophy.Representative fluorescent photomicrographs depicting immunolabeling for the synaptic protein, synaptophysin, in the (B) DG, (D) CA1 region of the hippocampus, and (F) prefrontal cortex of flour- and BSSG-treated animals 10 months following initial BSSG exposure. Immunolabeling for synaptophysinwas significantly reduced in the (A) DG and (C) CA1 region of the hippocampus, as well as (E) the prefrontal cortex at 10 months following initial BSSG exposure, as compared to controls. In the CA1 region, there was a slight, but significant, decline in synaptophysin immunodensity observed in controls, relative to earlier time points. Each bar represents the mean (± S.E.M., n = 9–10) optical density measured. ** sig. diff. from flour control, p < 0.001; ++ sig. diff. from 4 months, p < 0.001; ## sig. diff. from 6 months, p < 0.001; ∞∞ sig. diff. from 8 months, p < 0.001; ∞ p< 0.05.
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pone.0139694.g011: BSSG triggers hippocampal and cortical synaptic atrophy.Representative fluorescent photomicrographs depicting immunolabeling for the synaptic protein, synaptophysin, in the (B) DG, (D) CA1 region of the hippocampus, and (F) prefrontal cortex of flour- and BSSG-treated animals 10 months following initial BSSG exposure. Immunolabeling for synaptophysinwas significantly reduced in the (A) DG and (C) CA1 region of the hippocampus, as well as (E) the prefrontal cortex at 10 months following initial BSSG exposure, as compared to controls. In the CA1 region, there was a slight, but significant, decline in synaptophysin immunodensity observed in controls, relative to earlier time points. Each bar represents the mean (± S.E.M., n = 9–10) optical density measured. ** sig. diff. from flour control, p < 0.001; ++ sig. diff. from 4 months, p < 0.001; ## sig. diff. from 6 months, p < 0.001; ∞∞ sig. diff. from 8 months, p < 0.001; ∞ p< 0.05.

Mentions: In order to estimate degenerative axonal pathology in the hippocampus and cortex, we examined the synaptic protein, synaptophysin. No significant changes in synaptophysin immunodensity were observed until 10 months following initial BSSG exposure. At this time, BSSG-fed animals were found to have a significant reduction in immunolabeling of the hippocampal DG and CA1, as well as prefrontal cortex (DG: F1,71 = 172.61, p<0.0001, BSSG main effect; F3,71 = 83.40, p<0.0001, time main effect; F3,71 = 52.04, p<0.0001, interaction effect) (CA1: F1,71 = 140.04, p<0.0001, BSSG main effect; F3,71 = 259.56, p<0.0001, time main effect; F3,71 = 51.19, p<0.0001, interaction effect) (PFC: F1,71 = 64.58, p<0.0001, BSSG main effect; F3,71 = 33.05, p<0.0001, time main effect; F3,71 = 9.92, p<0.0001, interaction effect) (Fig 11).


The Progressive BSSG Rat Model of Parkinson's: Recapitulating Multiple Key Features of the Human Disease.

Van Kampen JM, Baranowski DC, Robertson HA, Shaw CA, Kay DG - PLoS ONE (2015)

BSSG triggers hippocampal and cortical synaptic atrophy.Representative fluorescent photomicrographs depicting immunolabeling for the synaptic protein, synaptophysin, in the (B) DG, (D) CA1 region of the hippocampus, and (F) prefrontal cortex of flour- and BSSG-treated animals 10 months following initial BSSG exposure. Immunolabeling for synaptophysinwas significantly reduced in the (A) DG and (C) CA1 region of the hippocampus, as well as (E) the prefrontal cortex at 10 months following initial BSSG exposure, as compared to controls. In the CA1 region, there was a slight, but significant, decline in synaptophysin immunodensity observed in controls, relative to earlier time points. Each bar represents the mean (± S.E.M., n = 9–10) optical density measured. ** sig. diff. from flour control, p < 0.001; ++ sig. diff. from 4 months, p < 0.001; ## sig. diff. from 6 months, p < 0.001; ∞∞ sig. diff. from 8 months, p < 0.001; ∞ p< 0.05.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4595214&req=5

pone.0139694.g011: BSSG triggers hippocampal and cortical synaptic atrophy.Representative fluorescent photomicrographs depicting immunolabeling for the synaptic protein, synaptophysin, in the (B) DG, (D) CA1 region of the hippocampus, and (F) prefrontal cortex of flour- and BSSG-treated animals 10 months following initial BSSG exposure. Immunolabeling for synaptophysinwas significantly reduced in the (A) DG and (C) CA1 region of the hippocampus, as well as (E) the prefrontal cortex at 10 months following initial BSSG exposure, as compared to controls. In the CA1 region, there was a slight, but significant, decline in synaptophysin immunodensity observed in controls, relative to earlier time points. Each bar represents the mean (± S.E.M., n = 9–10) optical density measured. ** sig. diff. from flour control, p < 0.001; ++ sig. diff. from 4 months, p < 0.001; ## sig. diff. from 6 months, p < 0.001; ∞∞ sig. diff. from 8 months, p < 0.001; ∞ p< 0.05.
Mentions: In order to estimate degenerative axonal pathology in the hippocampus and cortex, we examined the synaptic protein, synaptophysin. No significant changes in synaptophysin immunodensity were observed until 10 months following initial BSSG exposure. At this time, BSSG-fed animals were found to have a significant reduction in immunolabeling of the hippocampal DG and CA1, as well as prefrontal cortex (DG: F1,71 = 172.61, p<0.0001, BSSG main effect; F3,71 = 83.40, p<0.0001, time main effect; F3,71 = 52.04, p<0.0001, interaction effect) (CA1: F1,71 = 140.04, p<0.0001, BSSG main effect; F3,71 = 259.56, p<0.0001, time main effect; F3,71 = 51.19, p<0.0001, interaction effect) (PFC: F1,71 = 64.58, p<0.0001, BSSG main effect; F3,71 = 33.05, p<0.0001, time main effect; F3,71 = 9.92, p<0.0001, interaction effect) (Fig 11).

Bottom Line: Locomotor deficits developed gradually over time, initially appearing as locomotor asymmetry and developing into akinesia/bradykinesia, which was reversed by levodopa treatment.In addition to the progressive loss of TH+ cells in the substantia nigra, the appearance of proteinase K-resistant intracellular α-synuclein aggregates was also observed to develop progressively, appearing first in the olfactory bulb, then the striatum, the substantia nigra and, finally, hippocampal and cortical regions.The slowly progressive nature of this model, together with its construct, face and predictive validity, make it ideal for the screening of potential neuroprotective therapies for the treatment of PD.

View Article: PubMed Central - PubMed

Affiliation: Neurodyn Inc., 550 University Ave, Charlottetown, Prince Edward Island, C1A 4P3, Canada; Dept. Biomedical Science, University of Prince Edward Island, 550 University Ave, Charlottetown, Prince Edward Island, C1A 4P3, Canada.

ABSTRACT
The development of effective neuroprotective therapies for Parkinson's disease (PD) has been severely hindered by the notable lack of an appropriate animal model for preclinical screening. Indeed, most models currently available are either acute in nature or fail to recapitulate all characteristic features of the disease. Here, we present a novel progressive model of PD, with behavioural and cellular features that closely approximate those observed in patients. Chronic exposure to dietary phytosterol glucosides has been found to be neurotoxic. When fed to rats, β-sitosterol β-d-glucoside (BSSG) triggers the progressive development of parkinsonism, with clinical signs and histopathology beginning to appear following cessation of exposure to the neurotoxic insult and continuing to develop over several months. Here, we characterize the progressive nature of this model, its non-motor features, the anatomical spread of synucleinopathy, and response to levodopa administration. In Sprague Dawley rats, chronic BSSG feeding for 4 months triggered the progressive development of a parkinsonian phenotype and pathological events that evolved slowly over time, with neuronal loss beginning only after toxin exposure was terminated. At approximately 3 months following initiation of BSSG exposure, animals displayed the early emergence of an olfactory deficit, in the absence of significant dopaminergic nigral cell loss or locomotor deficits. Locomotor deficits developed gradually over time, initially appearing as locomotor asymmetry and developing into akinesia/bradykinesia, which was reversed by levodopa treatment. Late-stage cognitive impairment was observed in the form of spatial working memory deficits, as assessed by the radial arm maze. In addition to the progressive loss of TH+ cells in the substantia nigra, the appearance of proteinase K-resistant intracellular α-synuclein aggregates was also observed to develop progressively, appearing first in the olfactory bulb, then the striatum, the substantia nigra and, finally, hippocampal and cortical regions. The slowly progressive nature of this model, together with its construct, face and predictive validity, make it ideal for the screening of potential neuroprotective therapies for the treatment of PD.

No MeSH data available.


Related in: MedlinePlus