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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 the progressive loss of striatal DAT.(A) Representative fluorescent photomicrographs of dopamine transporter (DAT) immunostaining in the striatum 4, 6, 8, and 10 months following initial BSSG exposure. (B) Immunolabeling for DAT was significantly reduced, beginning as early as 4 months following initial BSSG exposure. Each bar represents the mean (± S.E.M., n = 9–10) optical density measured in 3 regions across 4 coronal sections through the striatum. (C) Asymmetrical loss of DAT immunolabeling in the striatum was observed at 4 and 6 months following initial BSSG exposure, with no significant hemispheric asymmetry observed at 8 or 10 months. Each bar represents the mean (± S.E.M., n = 9–10) hemispheric difference, expressed as a percentage of the most populated hemisphere. (D) Representative photomicrograph depicting asymmetry in DAT immunolabeling in the striatum 6 months following initial exposure to BSSG. ** 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.g007: BSSG triggers the progressive loss of striatal DAT.(A) Representative fluorescent photomicrographs of dopamine transporter (DAT) immunostaining in the striatum 4, 6, 8, and 10 months following initial BSSG exposure. (B) Immunolabeling for DAT was significantly reduced, beginning as early as 4 months following initial BSSG exposure. Each bar represents the mean (± S.E.M., n = 9–10) optical density measured in 3 regions across 4 coronal sections through the striatum. (C) Asymmetrical loss of DAT immunolabeling in the striatum was observed at 4 and 6 months following initial BSSG exposure, with no significant hemispheric asymmetry observed at 8 or 10 months. Each bar represents the mean (± S.E.M., n = 9–10) hemispheric difference, expressed as a percentage of the most populated hemisphere. (D) Representative photomicrograph depicting asymmetry in DAT immunolabeling in the striatum 6 months following initial exposure to BSSG. ** 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: Striatal innervation by nigrostriatal neurons was determined by densitometric measurement of DAT immunolabeling in the striatum. DAT immunolabeling was significantly reduced in the striatum following exposure to BSSG, beginning at 4 months following initial BSSG exposure and progressing in a time-dependent manner (F1,71 = 185.04, p<0.0001, BSSG main effect; F3,71 = 9.26, p<0.0001, time main effect; F3,71 = 1.28, p = 0.288, interaction effect) (Fig 7). No significant regional variation was observed within the striatum. Similar to the loss of TH+ neurons in the SNc, striatal DAT immunolabeling exhibited hemispheric asymmetry following BSSG exposure, peaking at 4 and 6 months following initial exposure (F1,71 = 259.27, p<0.0001, BSSG main effect; F3,71 = 45.36, p<0.0001, time main effect; F3,71 = 61.83, p<0.0001, interaction effect). By contrast, no significant difference in hemispheric asymmetry was apparent at 8 or 10 months following initial BSSG exposure. Although hemispheric asymmetry was not lateralized to the same hemisphere in all animals, where significant asymmetry was apparent, decreases in nigral and striatal immunolabeling were lateralized to the same hemisphere in each animal.


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 the progressive loss of striatal DAT.(A) Representative fluorescent photomicrographs of dopamine transporter (DAT) immunostaining in the striatum 4, 6, 8, and 10 months following initial BSSG exposure. (B) Immunolabeling for DAT was significantly reduced, beginning as early as 4 months following initial BSSG exposure. Each bar represents the mean (± S.E.M., n = 9–10) optical density measured in 3 regions across 4 coronal sections through the striatum. (C) Asymmetrical loss of DAT immunolabeling in the striatum was observed at 4 and 6 months following initial BSSG exposure, with no significant hemispheric asymmetry observed at 8 or 10 months. Each bar represents the mean (± S.E.M., n = 9–10) hemispheric difference, expressed as a percentage of the most populated hemisphere. (D) Representative photomicrograph depicting asymmetry in DAT immunolabeling in the striatum 6 months following initial exposure to BSSG. ** 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.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4595214&req=5

pone.0139694.g007: BSSG triggers the progressive loss of striatal DAT.(A) Representative fluorescent photomicrographs of dopamine transporter (DAT) immunostaining in the striatum 4, 6, 8, and 10 months following initial BSSG exposure. (B) Immunolabeling for DAT was significantly reduced, beginning as early as 4 months following initial BSSG exposure. Each bar represents the mean (± S.E.M., n = 9–10) optical density measured in 3 regions across 4 coronal sections through the striatum. (C) Asymmetrical loss of DAT immunolabeling in the striatum was observed at 4 and 6 months following initial BSSG exposure, with no significant hemispheric asymmetry observed at 8 or 10 months. Each bar represents the mean (± S.E.M., n = 9–10) hemispheric difference, expressed as a percentage of the most populated hemisphere. (D) Representative photomicrograph depicting asymmetry in DAT immunolabeling in the striatum 6 months following initial exposure to BSSG. ** 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: Striatal innervation by nigrostriatal neurons was determined by densitometric measurement of DAT immunolabeling in the striatum. DAT immunolabeling was significantly reduced in the striatum following exposure to BSSG, beginning at 4 months following initial BSSG exposure and progressing in a time-dependent manner (F1,71 = 185.04, p<0.0001, BSSG main effect; F3,71 = 9.26, p<0.0001, time main effect; F3,71 = 1.28, p = 0.288, interaction effect) (Fig 7). No significant regional variation was observed within the striatum. Similar to the loss of TH+ neurons in the SNc, striatal DAT immunolabeling exhibited hemispheric asymmetry following BSSG exposure, peaking at 4 and 6 months following initial exposure (F1,71 = 259.27, p<0.0001, BSSG main effect; F3,71 = 45.36, p<0.0001, time main effect; F3,71 = 61.83, p<0.0001, interaction effect). By contrast, no significant difference in hemispheric asymmetry was apparent at 8 or 10 months following initial BSSG exposure. Although hemispheric asymmetry was not lateralized to the same hemisphere in all animals, where significant asymmetry was apparent, decreases in nigral and striatal immunolabeling were lateralized to the same hemisphere in each animal.

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