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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 significantly reduced locomotor activity and coordination.(A) As early as 6 months following initiation of BSSG exposure, animals displayed a time-dependent reduction in locomotor activity, as assessed by the distance travelled over a 1 hour period. (B) Locomotor activity was significantly reduced to approximately 82%, 67%, 56%, and 56% of sham controls, at 4, 6, 8, and 10 months following initiation of BSSG exposure, respectively. Each bar represents the (A) mean (± S.E.M., n = 18–20) distance traveled in 1 hour or (B) mean (± S.E.M., n = 18–20) percent of sham control. (C) At 6, 8, and 10 months following initiation of BSSG exposure, animals displayed progressive deficits in locomotor coordination, as assessed by the number of foot slips when tested in the foot misplacement apparatus. The total number of foot slips was significantly greater than sham controls at all three time points. Each bar represents the mean (± S.E.M., n = 18–20) number of foot slips recorded. (D) Animals were also progressively slower to traverse the horizontal ladder in the foot misplacement apparatus. Each bar represents the mean (± S.E.M., n = 18–20) time (sec.) to traverse the ladder. ** sig. diff. from flour control, p < 0.001; ++ sig. diff. from 4 months, p < 0.001; ## sig. diff. from 6 months, p< 0.001; # p< 0.05.
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pone.0139694.g002: BSSG significantly reduced locomotor activity and coordination.(A) As early as 6 months following initiation of BSSG exposure, animals displayed a time-dependent reduction in locomotor activity, as assessed by the distance travelled over a 1 hour period. (B) Locomotor activity was significantly reduced to approximately 82%, 67%, 56%, and 56% of sham controls, at 4, 6, 8, and 10 months following initiation of BSSG exposure, respectively. Each bar represents the (A) mean (± S.E.M., n = 18–20) distance traveled in 1 hour or (B) mean (± S.E.M., n = 18–20) percent of sham control. (C) At 6, 8, and 10 months following initiation of BSSG exposure, animals displayed progressive deficits in locomotor coordination, as assessed by the number of foot slips when tested in the foot misplacement apparatus. The total number of foot slips was significantly greater than sham controls at all three time points. Each bar represents the mean (± S.E.M., n = 18–20) number of foot slips recorded. (D) Animals were also progressively slower to traverse the horizontal ladder in the foot misplacement apparatus. Each bar represents the mean (± S.E.M., n = 18–20) time (sec.) to traverse the ladder. ** sig. diff. from flour control, p < 0.001; ++ sig. diff. from 4 months, p < 0.001; ## sig. diff. from 6 months, p< 0.001; # p< 0.05.

Mentions: Locomotor deficits first appeared in the form of locomotor asymmetry. Animals were challenged with the dopamine releasing agent, methamphetamine (2 mg/kg, i.p.), which triggered a rotational response. Animals treated with BSSG displayed significantly more net rotations than controls at 4 months following initial toxin exposure (F1,35 = 188.59, p<0.0001, BSSG main effect; F1,35 = 124.89, p<0.0001, time main effect; F1,35 = 188.29, p<0.0001, interaction effect) (Fig 1B). Following post-mortem analysis, it was confirmed that, observed rotations occurred ipsilateral to the hemisphere of greatest striatal atrophy. However, no significant increase in net rotations was observed at 10 months, suggesting that locomotor asymmetry is an early feature of this model, with motor deficits progressing to become bilateral over time. In an open field, locomotor activity, measured as the distance traveled in one hour, was significantly reduced, beginning as early as 6 months following initial toxin exposure, as compared to controls (F1,38 = 98.75, p<0.0001, BSSG main effect; F3,117 = 68.57, p<0.0001, time main effect; F3,117 = 3.53, p = 0.0173, interaction effect) (Fig 2A). This deficit worsened over time, with significantly less locomotor activity observed at 10 months, as compared to 6 months. There appeared to be a slight age-related decrease in locomotor activity, overall, and this decline was significantly potentiated in BSSG-treated animals (Fig 2B). Locomotor coordination was also impaired following BSSG exposure. BSSG-treated animals displayed significantly more foot slips while traversing a horizontal ladder (F1,39 = 164.19, p<0.0001, BSSG main effect; F2,80 = 29.44, p<0.0001, time main effect; F2,80 = 5.37, p = 0.0066, interaction effect) (Fig 2C). This deficit first appeared at 6 months following initial toxin exposure and significantly worsened by 10 months. The time to traverse the ladder also increased following BSSG exposure (F1,39 = 83.39, p<0.0001, BSSG main effect; F2,80 = 108.96, p<0.0001, time main effect; F2,80 = 2.96, p<0.0001, interaction effect) (Fig 2D).


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 significantly reduced locomotor activity and coordination.(A) As early as 6 months following initiation of BSSG exposure, animals displayed a time-dependent reduction in locomotor activity, as assessed by the distance travelled over a 1 hour period. (B) Locomotor activity was significantly reduced to approximately 82%, 67%, 56%, and 56% of sham controls, at 4, 6, 8, and 10 months following initiation of BSSG exposure, respectively. Each bar represents the (A) mean (± S.E.M., n = 18–20) distance traveled in 1 hour or (B) mean (± S.E.M., n = 18–20) percent of sham control. (C) At 6, 8, and 10 months following initiation of BSSG exposure, animals displayed progressive deficits in locomotor coordination, as assessed by the number of foot slips when tested in the foot misplacement apparatus. The total number of foot slips was significantly greater than sham controls at all three time points. Each bar represents the mean (± S.E.M., n = 18–20) number of foot slips recorded. (D) Animals were also progressively slower to traverse the horizontal ladder in the foot misplacement apparatus. Each bar represents the mean (± S.E.M., n = 18–20) time (sec.) to traverse the ladder. ** sig. diff. from flour control, p < 0.001; ++ sig. diff. from 4 months, p < 0.001; ## sig. diff. from 6 months, p< 0.001; # p< 0.05.
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Related In: Results  -  Collection

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pone.0139694.g002: BSSG significantly reduced locomotor activity and coordination.(A) As early as 6 months following initiation of BSSG exposure, animals displayed a time-dependent reduction in locomotor activity, as assessed by the distance travelled over a 1 hour period. (B) Locomotor activity was significantly reduced to approximately 82%, 67%, 56%, and 56% of sham controls, at 4, 6, 8, and 10 months following initiation of BSSG exposure, respectively. Each bar represents the (A) mean (± S.E.M., n = 18–20) distance traveled in 1 hour or (B) mean (± S.E.M., n = 18–20) percent of sham control. (C) At 6, 8, and 10 months following initiation of BSSG exposure, animals displayed progressive deficits in locomotor coordination, as assessed by the number of foot slips when tested in the foot misplacement apparatus. The total number of foot slips was significantly greater than sham controls at all three time points. Each bar represents the mean (± S.E.M., n = 18–20) number of foot slips recorded. (D) Animals were also progressively slower to traverse the horizontal ladder in the foot misplacement apparatus. Each bar represents the mean (± S.E.M., n = 18–20) time (sec.) to traverse the ladder. ** sig. diff. from flour control, p < 0.001; ++ sig. diff. from 4 months, p < 0.001; ## sig. diff. from 6 months, p< 0.001; # p< 0.05.
Mentions: Locomotor deficits first appeared in the form of locomotor asymmetry. Animals were challenged with the dopamine releasing agent, methamphetamine (2 mg/kg, i.p.), which triggered a rotational response. Animals treated with BSSG displayed significantly more net rotations than controls at 4 months following initial toxin exposure (F1,35 = 188.59, p<0.0001, BSSG main effect; F1,35 = 124.89, p<0.0001, time main effect; F1,35 = 188.29, p<0.0001, interaction effect) (Fig 1B). Following post-mortem analysis, it was confirmed that, observed rotations occurred ipsilateral to the hemisphere of greatest striatal atrophy. However, no significant increase in net rotations was observed at 10 months, suggesting that locomotor asymmetry is an early feature of this model, with motor deficits progressing to become bilateral over time. In an open field, locomotor activity, measured as the distance traveled in one hour, was significantly reduced, beginning as early as 6 months following initial toxin exposure, as compared to controls (F1,38 = 98.75, p<0.0001, BSSG main effect; F3,117 = 68.57, p<0.0001, time main effect; F3,117 = 3.53, p = 0.0173, interaction effect) (Fig 2A). This deficit worsened over time, with significantly less locomotor activity observed at 10 months, as compared to 6 months. There appeared to be a slight age-related decrease in locomotor activity, overall, and this decline was significantly potentiated in BSSG-treated animals (Fig 2B). Locomotor coordination was also impaired following BSSG exposure. BSSG-treated animals displayed significantly more foot slips while traversing a horizontal ladder (F1,39 = 164.19, p<0.0001, BSSG main effect; F2,80 = 29.44, p<0.0001, time main effect; F2,80 = 5.37, p = 0.0066, interaction effect) (Fig 2C). This deficit first appeared at 6 months following initial toxin exposure and significantly worsened by 10 months. The time to traverse the ladder also increased following BSSG exposure (F1,39 = 83.39, p<0.0001, BSSG main effect; F2,80 = 108.96, p<0.0001, time main effect; F2,80 = 2.96, p<0.0001, interaction effect) (Fig 2D).

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