Investigation of possible neuroprotective effect of brimonidine in a alphasynucleinopathy parkinson's disease model created by intracerebroventricular plasmid and preformed fibril injection in rats

It was reported that central alpha-synuclein pre-formed fibril administration in rats caused alpha-synucleinopathy within 6 months and was suggested as a rat Parkinson's disease model. In this thesis, we hypothetized that alpha-synucleinopathy formation process would be shortened by the application of plasmid containing mRNA encoding alpha-synuclein protein 4 weeks before the application of intracerebroventricular alpha-synuclein pre-formed fibril in rats. In the process various neuropsychopharmacological tests to assess the cognitive, motor, and non-motor symptoms expected from a rat Parkinson's disease model were examine. In addition, as a secondary aim, the possible effect of the α2 adrenergic receptor agonist brimonidine, which has previously been shown to have neuroprotective effects on retinal ganglion cells, was evaluated on this model. In this thesis study, Sprague Dawley rats (250-300 g, 4 months old, n=30) of both sexes were used. Rats were randomly distributed into 5 homogeneous groups with equal sex distribution (n=6). These groups were formed as control, sham, alpha-synuclein, alpha-synuclein + brimonidine and brimonidine groups. Behavioral tests were performed 2 and 4 months after the end of the injections to assess the time dependence of the effects. Anxiety in rats was evaluated with open field and elevated plus maze tests, and learning-memory performance was evaluated with new object recognition and Morris water maze tests. Vertical grid test, horizontal staircase test and rot-a-rod test were used to evaluate motor coordination. The hot plate test was used to evaluate non-motor autonomic dysfunction. Although the anxiety assessed with the open field test was higher in the alpha-synuclein group at 2 months, it did not show a significant difference between the groups with the elevated plus maze test. In the alpha-synuclein group, memory performance as assessed by new object recognition and Morris water maze tests was found to be impaired at both time points. While vertical grid test, horizontal staircase test showed that motor coordination worsened in the alpha-synuclein group at both time points, rod-a-rod test showed that motor discoordination worsened especially at 4 months. Findings of the hot plate test based on the delay in the response time to the pain stimulus again determined that autonomic dysfunction developed in the alpha-synuclein group. In this thesis study, brimonidine, whose possible neuroprotective effect was evaluated, did not significantly reverse any worsening due to alpha-synuclein administration, except for autonomic dysfunction. In this thesis, it was concluded that intracerebroventricular plasmid pre-administration shortened the formation process of the rat Parkinson's disease model due to possible alpha-synuclein-induced alpha-synucleinopathy, as assessed by motor and non-motor findings.