Limits...
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 intoxication impairs spatial working memory.At 10 months following initiation of BSSG exposure, animals displayed significant impairment in both (A) reference and (B) working spatial memory, as assessed by their performance in a radial arm maze. Reference memory errors were defined as entries into arms that were never baited. Working memory errors were defined as entries into previously visited arms. Each point represents the mean (± S.E.M., n = 18–20) number of errors. (C) Spontaneous alternation in a T-maze was also impaired 10 months following initial BSSG exposure, as compared to controls. However, no such deficit was yet apparent at 4 months. ** sig. diff. from sham control, p< 0.001; * p<0.05.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4595214&req=5

pone.0139694.g004: BSSG intoxication impairs spatial working memory.At 10 months following initiation of BSSG exposure, animals displayed significant impairment in both (A) reference and (B) working spatial memory, as assessed by their performance in a radial arm maze. Reference memory errors were defined as entries into arms that were never baited. Working memory errors were defined as entries into previously visited arms. Each point represents the mean (± S.E.M., n = 18–20) number of errors. (C) Spontaneous alternation in a T-maze was also impaired 10 months following initial BSSG exposure, as compared to controls. However, no such deficit was yet apparent at 4 months. ** sig. diff. from sham control, p< 0.001; * p<0.05.

Mentions: While locomotor dysfunction is the most prominent feature of PD, non-motor features, such as dementia, are often more problematic. The majority of PD patients will develop dementia within 12 years [15], which is the primary cause of institutionalization of these patients. Here, BSSG intoxicated animals were tested for the development of cognitive deficits Animals exposed to BSSG did display some signs of cognitive impairment. At 4 and 10 months following initiation of BSSG exposure, animals were tested for spontaneous alternation in a T-maze (Fig 4C). Spontaneous alternation is considered a test of short-term working memory dependent on hippocampus, septum, basal forebrain, and prefrontal cortex [16]. Since this test does not require training or food-restriction, testing could be performed at both early and late time points without concern of influencing pathological development or behavioural response. Using this test, animals showed no cognitive impairment at 4 months but did show a significant impairment at 10 months following initial BSSG exposure (F1,39 = 433.92, p<0.0001, BSSG main effect; F1,40 = 559.45, p<0.0001, time main effect; F1,40 = 575.67, p<0.0001, interaction effect). At this time point, BSSG-intoxicated animals also displayed significant deficits in both reference and spatial working memory, as assessed by the eight arm radial arm maze (F1,37 = 38.89, p<0.0001, BSSG main effect; F4,162 = 295.26, p<0.0001, time main effect; F4,152 = 42.56, p<0.0001, interaction effect) (Fig 4A and 4B). Using this test, BSSG-fed animals were more likely to enter arms that were never baited. They also were more likely to re-enter arms they had already visited.


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 intoxication impairs spatial working memory.At 10 months following initiation of BSSG exposure, animals displayed significant impairment in both (A) reference and (B) working spatial memory, as assessed by their performance in a radial arm maze. Reference memory errors were defined as entries into arms that were never baited. Working memory errors were defined as entries into previously visited arms. Each point represents the mean (± S.E.M., n = 18–20) number of errors. (C) Spontaneous alternation in a T-maze was also impaired 10 months following initial BSSG exposure, as compared to controls. However, no such deficit was yet apparent at 4 months. ** sig. diff. from sham control, p< 0.001; * p<0.05.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0139694.g004: BSSG intoxication impairs spatial working memory.At 10 months following initiation of BSSG exposure, animals displayed significant impairment in both (A) reference and (B) working spatial memory, as assessed by their performance in a radial arm maze. Reference memory errors were defined as entries into arms that were never baited. Working memory errors were defined as entries into previously visited arms. Each point represents the mean (± S.E.M., n = 18–20) number of errors. (C) Spontaneous alternation in a T-maze was also impaired 10 months following initial BSSG exposure, as compared to controls. However, no such deficit was yet apparent at 4 months. ** sig. diff. from sham control, p< 0.001; * p<0.05.
Mentions: While locomotor dysfunction is the most prominent feature of PD, non-motor features, such as dementia, are often more problematic. The majority of PD patients will develop dementia within 12 years [15], which is the primary cause of institutionalization of these patients. Here, BSSG intoxicated animals were tested for the development of cognitive deficits Animals exposed to BSSG did display some signs of cognitive impairment. At 4 and 10 months following initiation of BSSG exposure, animals were tested for spontaneous alternation in a T-maze (Fig 4C). Spontaneous alternation is considered a test of short-term working memory dependent on hippocampus, septum, basal forebrain, and prefrontal cortex [16]. Since this test does not require training or food-restriction, testing could be performed at both early and late time points without concern of influencing pathological development or behavioural response. Using this test, animals showed no cognitive impairment at 4 months but did show a significant impairment at 10 months following initial BSSG exposure (F1,39 = 433.92, p<0.0001, BSSG main effect; F1,40 = 559.45, p<0.0001, time main effect; F1,40 = 575.67, p<0.0001, interaction effect). At this time point, BSSG-intoxicated animals also displayed significant deficits in both reference and spatial working memory, as assessed by the eight arm radial arm maze (F1,37 = 38.89, p<0.0001, BSSG main effect; F4,162 = 295.26, p<0.0001, time main effect; F4,152 = 42.56, p<0.0001, interaction effect) (Fig 4A and 4B). Using this test, BSSG-fed animals were more likely to enter arms that were never baited. They also were more likely to re-enter arms they had already visited.

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