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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 early olfactory deficits and locomotor asymmetry.(A) Olfactory sensitivity was assessed by comparing the time spent exploring a vanilla solution versus time spent exploring a water-only solution. Lack of detection was defined by equal investigation between the odour solution and the water control (ratio = 1). Control animals spent more time in the vicinity of the odour, as compared to water alone. As early as 3 months following initiation of BSSG intoxication, animals spent a significantly smaller proportion of their time exploring the odour and, by 8 months, displayed little evidence of discrimination. Each bar represents the mean (± S.E.M., n = 18–20) ratio of exploration time. (B) At 4 months following initiation of BSSG exposure, animals displayed locomotor asymmetry, as assessed by methamphetamine (2 mg/kg, i.p.)-induced rotations. No significant increase in drug-induced rotations was observed 10 months following initial BSSG exposure. Each bar represents the mean (± S.E.M., n = 10) net rotations recorded in 1 hour. ** sig. diff. from flour control, p < 0.001, * p < .05.
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pone.0139694.g001: BSSG triggers early olfactory deficits and locomotor asymmetry.(A) Olfactory sensitivity was assessed by comparing the time spent exploring a vanilla solution versus time spent exploring a water-only solution. Lack of detection was defined by equal investigation between the odour solution and the water control (ratio = 1). Control animals spent more time in the vicinity of the odour, as compared to water alone. As early as 3 months following initiation of BSSG intoxication, animals spent a significantly smaller proportion of their time exploring the odour and, by 8 months, displayed little evidence of discrimination. Each bar represents the mean (± S.E.M., n = 18–20) ratio of exploration time. (B) At 4 months following initiation of BSSG exposure, animals displayed locomotor asymmetry, as assessed by methamphetamine (2 mg/kg, i.p.)-induced rotations. No significant increase in drug-induced rotations was observed 10 months following initial BSSG exposure. Each bar represents the mean (± S.E.M., n = 10) net rotations recorded in 1 hour. ** sig. diff. from flour control, p < 0.001, * p < .05.

Mentions: Among a variety of non-motor symptoms observed in PD, hyposmia typically precedes the onset of motor features in PD in approximately 70–95% of patients [13, 14]. Here, animals were tested for olfactory sensitivity using a simple olfactory detection protocol that did not require extensive training. Using this protocol, we found that the ratio of time spent exploring an odour versus plain drinking water was significantly reduced in BSSG-fed animals across all time points, beginning as early as 3 months following initial exposure to the toxin (F1,39 = 649.72, p<0.0001) (Fig 1A). Control animals did not display any variability across the time points studied. These data suggest an early and persistent deficit in olfactory sensitivity.


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 early olfactory deficits and locomotor asymmetry.(A) Olfactory sensitivity was assessed by comparing the time spent exploring a vanilla solution versus time spent exploring a water-only solution. Lack of detection was defined by equal investigation between the odour solution and the water control (ratio = 1). Control animals spent more time in the vicinity of the odour, as compared to water alone. As early as 3 months following initiation of BSSG intoxication, animals spent a significantly smaller proportion of their time exploring the odour and, by 8 months, displayed little evidence of discrimination. Each bar represents the mean (± S.E.M., n = 18–20) ratio of exploration time. (B) At 4 months following initiation of BSSG exposure, animals displayed locomotor asymmetry, as assessed by methamphetamine (2 mg/kg, i.p.)-induced rotations. No significant increase in drug-induced rotations was observed 10 months following initial BSSG exposure. Each bar represents the mean (± S.E.M., n = 10) net rotations recorded in 1 hour. ** sig. diff. from flour control, p < 0.001, * p < .05.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4595214&req=5

pone.0139694.g001: BSSG triggers early olfactory deficits and locomotor asymmetry.(A) Olfactory sensitivity was assessed by comparing the time spent exploring a vanilla solution versus time spent exploring a water-only solution. Lack of detection was defined by equal investigation between the odour solution and the water control (ratio = 1). Control animals spent more time in the vicinity of the odour, as compared to water alone. As early as 3 months following initiation of BSSG intoxication, animals spent a significantly smaller proportion of their time exploring the odour and, by 8 months, displayed little evidence of discrimination. Each bar represents the mean (± S.E.M., n = 18–20) ratio of exploration time. (B) At 4 months following initiation of BSSG exposure, animals displayed locomotor asymmetry, as assessed by methamphetamine (2 mg/kg, i.p.)-induced rotations. No significant increase in drug-induced rotations was observed 10 months following initial BSSG exposure. Each bar represents the mean (± S.E.M., n = 10) net rotations recorded in 1 hour. ** sig. diff. from flour control, p < 0.001, * p < .05.
Mentions: Among a variety of non-motor symptoms observed in PD, hyposmia typically precedes the onset of motor features in PD in approximately 70–95% of patients [13, 14]. Here, animals were tested for olfactory sensitivity using a simple olfactory detection protocol that did not require extensive training. Using this protocol, we found that the ratio of time spent exploring an odour versus plain drinking water was significantly reduced in BSSG-fed animals across all time points, beginning as early as 3 months following initial exposure to the toxin (F1,39 = 649.72, p<0.0001) (Fig 1A). Control animals did not display any variability across the time points studied. These data suggest an early and persistent deficit in olfactory sensitivity.

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