Rat are intoxicated with beta-sitosterol- beta-D-glucoside (BSSG) administered in the form of flour pellets.
Toxin: b-sitosterol- b-d-glucoside (BSSG)
Corresponding human genotype: idiopathic Parkinson’s disease.
References: Van Kampen 2015, Van Kampen 2017
The toxin is given to 2-3 months old rats per os using BSSG-containing pellets. Rats are put on a restriction diet 8-12h before BSSG pellet feeding to maximize gastrointestinal consumption. Animals are given ad libidum access to normal chow 2 hours after beginning of BSSG-pellet consumption. Food is completely removed 8 hours later. BSSG-Pellets are fed to the animals 5 days a week during 16 weeks. After this period the diet is switched to normal pellets and the PD phenotype develops over a 4 to 6-month time-period.
This diet regimen does not induce any weight loss in BSSG-treated animals compared to controls animals.
- 4-month post treatment initiation (=at the end of the BSSG pellet feeding period): no changes in the number of TH-positive neurons in the SN is observed. A lateralized loss of DAT immunostaining is observed in the striatum.
- 6- 10-month post treatment initiation (=2-4 months after the end of BSSG-pellet feeding period): progressive development of an initially asymmetric loss of TH-positive neurons in the SN, that is predominant in one hemisphere. Maximal asymmetry is observed at 6 months.
Cell loss reaches a peak at 10 months (75-80% cell loss).
Progressive loss of DAT expression in striatal terminals is observed first unilaterally (4 months) and then bilaterally peaking at 8 months.
Hemispheric asymmetry is not lateralized to the same hemisphere in all animals, but is constant in each animal (reduction of dopaminergic marker initiate in SN and striatum of the same hemisphere)
- not reported
- 4-month post treatment initiation: intracellular alpha-synuclein inclusions are observed only in the olfactory
- 6-month post treatment initiation: inclusions are observed in the striatum and to a lesser extent in the SN.
- 8-10-month post treatment initiation: intracellular (in the SN) and extracellular inclusions are detected. No inculsions are observed at that time in cortex or hippocampus.
- >10-month post treatment initiation: inclusions are present in the cortex (entorhinal and primary motor region) and the hippocampus (DG and CA1)
- 4-month post treatment initiation (=end of BSSG pellet feeding period): no obvious motor symptoms are observed. Locomotor asymmetry is observed only following amphetamine challenge.
- 6-10-month post treatment initiation: A progressive decline in locomotor activity (open field) that worsens over time is observed. More footslips are observed in the horizontal ladder test (6 months). Impairment in skill reaching (staircase step test) is detected.
Response to dopaminergic treatment
- 8-10 month post treatment initiation: All motor behaviour are completely reversed by treatment with levodopa.
Non motor Behaviours
- Olfactory dysfunction: deficits are observed 3 months after treatment initiation before the detection of any motor symptoms. The olfactory dysfunction persists throughout the lifespan of the animals
- No cognitive impairment is observed at 4-month post treatment initiation. A significant impairment is observed at 10-month post treatment initiation in the T-maze test (short term working memory)
- not reported.
- 4-month post treatment initiation: lateralized increase in microglial activation (immunostaining) is observed in the SN.
- 6-10-month post treatment initiation: persistence of microglial activation is observed with a reduction in the asymmetry. Both hemisphere show similar levels of activation.